Bioactive peptides in anterior pituitary cells

Peptides, Vol. 15, No. 3, pp. 547-582, 1994 Copyright © 1994 ElsevierScienceLtd Printed in the USA. All rights reserved 0196-9781/94 $6.00 + .00

Pergamon 0196-9781(93)E0020-R

REVIEW

Bioactive Peptides in Anterior Pituitary Cells H. H O U B E N l A N D

C. D E N E F 2

University of Leuven, School of Medicine, Department of Pharmacology, Laboratory of Cell Pharmacology, Campus Gasthuisberg O/N, Herestraat 49, 3000 Leuven, Belgium R e c e i v e d 23 J u n e 1993 HOUBEN, H. AND C. DENEF. Bioactivepeptides in anteriorpituitary cells. PEPTIDES 15(3) 547-582, 1994.--The anterior pituitary (AP) has been shown to contain a wide variety of bioactive peptides: brain-gut peptides, growth factors, hypothalamic releasing factors, posterior lobe peptides, opioids, and various other peptides. The localization of most of these peptides was first established by immunocytochemical methods and some of the peptides were localized in identified cell types. Although intracellular localization of a peptide may be the consequence of internalization from the plasma compartment, there is evidence for local synthesis of most of these peptides in the AP based on the identification of their messenger-RNA (mRNA). In several cases the release of the peptide from the AP cell has been shown and regulation of synthesis, storage and release have also been described. Because the amount of most of the AP peptides is very low (except for POMC peptides and galanin), endocrine functions are not expected. There is more evidence for paracrine, autocrine, or intracrine roles in growth, differentiation, and regeneration, or in the control of hormone release. To demonstrate such functions, in vitro AP experiments have been designed to avoid the interference of hypothalamic or peripheral hormones. The strategy is first to show a direct effect of the peptide after adding it to the in vitro system and, secondly, to explore if the endogenous AP peptide has a similar action by using blockers of peptide receptors or antisera immunoneutralizing the peptide. Peptides

Anterior pituitary

Local control

peptides. This information is important to thrash out the local function of the peptides. Although in some cases effects of the peptides on m R N A levels, on cell growth, or on cellular differentiation have been studied, most research concerning the functions of AP peptides has been devoted to their effects on hormone release. However, the results of this research are often confusing because the effects of several peptides appear to depend on the test system used, the animal species, the hormonal conditions, and so on. As far as data are available, we will discuss for each peptide the next items in the following order: description of the peptide, evidence for presence and local production in the AP, cellular localization, regulation ofpeptide content, release of the peptide by AP cells, presence of its receptors in the AP, effects on horm o n e release and synthesis, other effects of the peptide in the AP, and, finally, data on its possible local function.

C O N T R O L of cellular activity by paracrine and autocrine interactions between cells of the same tissue has gained considerable attention. Several peptides that have been detected in low amounts in various tissues may contribute to this complex network of intratissue regulation. The present review deals with peptides that have been demonstrated in the anterior pituitary (AP) by immunological and/or molecular biological methods. Available evidence for the local synthesis o f A P peptides is based on the identification of the peptide m R N A , on the finding that the peptide is maintained in AP cell cultures, and on indications that labeled amino acids are incorporated into the peptide by AP cells. We also review the eflbrts that have been devoted to the determination of the AP cell type containing each of the peptides. This information could give an indication of the possible function of the peptides because AP cells are traditionally classified according to the hormone they secrete: lactotrophs, somatotrophs, thyrotrophs, gonadotrophs, corticotrophs, and folliculo-stellate cells (the latter secreting no traditional hormone). The present study also deals with the regulatory control of the a m o u n t of peptides stored in the AP. Data on the release of the peptides and on the presence of peptide receptors in AP tissue will be described, as well as data on the biological responses to these

BRAIN-GUT PEPTIDES (TABLES I-3)

Vasoactive Intestinal Peptide Vasoactive intestinal peptide (VIP), an intestinal peptide considered as a putative hypothalamic releasing factor for prolactin (PRL), is well characterized as far as its presence and

Research associate of the Belgian fund for Scientific Research. 2 Requests for reprints should be addressed to C. Denef.

547

548

HOUBEN AND DENEF

TABLE 1 PRESENCE OF BRAIN-GUT PEPTIDES IN AP Peptide VIP

SP

IR mRNA Labeled amino acid incorporation Remains in culture IR ¢3and 7 mRNA

Galanin

IR mRNA

NPY

1R mRNA IR mRNA Stalk transection IR pro-GRP-IR Remains 4 weeks in culture mRNA IR mRNA IR mRNA (P, AtT20) Propeptides IR IR IR mRNA

NT

BBN/GRP

RTN/NMB Gastrin/CCK

Secretin Motilin NMU

Cell Type Containing Peptide

Evidence for Presenceor Synthesis

Release of Peptidc by AP Cells

L ~ not in L Stellate cells

Basal '~ K +, TRH, IGF, GRF

L, G *-~ S, T (rat) T (human, guinea pig) Nerve fiber GH3 L, S, T C (human)

Basal ~ K+

T G, S, C, L not T G. T

C, L S GH3, AtT2o

Receptors for Peptide in AP + L GH3 AtTzo 4

Basal ~ E2, TRH, GRF ~, DA, SRIF ~+ Basal f K+

+

+ GH4CI

T (rat, mouse) G (human) C

S C

Summary of data on the presence of peptides in the AP. Evidence for presence or synthesis: the peptide has been demonstrated in AP based on its immunoreactivity (IR); mRNA encoding the peptide is found in the AP (mRNA); labeled amino acids are incorporated in the peptide by AP cells (labeled amino acid incorporation); the peptide is still detectable in AP after stalk transection (stalk transection); the peptide is detectable in AP cell cultures (remains present in culture): propeptides are detected in AP (propeptides) or the peptide was isolated from AP tissue (peptide isolation). P indicates data referring to whole pituitary. Cell type containing peptide: in this column we indicate all cell types that have been reported to contain the peptide or its mRNA. The abbreviations for lactotroph (L), somatotroph (S), gonadotroph (G), corticotroph (C), thyrotroph (T), and folliculo-stellate cell (FS) are used. Some peptides were found in (nerve) fibers in the AP, which is indicated as well. Release of peptide by AP cells: we indicate if AP cells display a basal release of the peptide (basal); we show substances enhancing the peptide release (behind ~') and substances decreasing the release (behind ~,).Standard abbreviations are used for the peptides and for dopamine (DA), estradiol (E2), dexamethasone (Dex). Receptors for peptide in AP: here we indicate whether receptors are detectable (+) or undetectable ( ) in AP. If known we indicate on which AP cell type receptors are found. In some cases the species or cell line containing or releasing the peptide or carrying the receptor is indicated. The indication ~-~ is placed between conflicting data and ? indicates a less certain statement. References for the data can be found in the text in the paragraph concerning each peptide.

function in the AP are concerned. Vasoactive intestinal peptide immunoreactivity (IR) has been d e m o n s t r a t e d in rat, dog, and porcine AP cells by extraction and r a d i o i m m u n o a s s a y o f the peptide and by immunocytochemistry (8,246,388). Several years ago direct evidence for local synthesis o f V1P in the AP was given by demonstrating the incorporation o f [3H]leucine into the peptide (8). Additional evidence was found recently by showing that VIP-IR is m a i n t a i n e d in AP cell cultures and in pituitaries implanted u n d e r the kidney capsule (246). Furthermore, VIP m R N A was d e m o n s t r a t e d in the A P by Northern blot analysis (426). Because VIP and peptide histidine isoleucine (PHI) are encoded in the same precursor, PHI synthesis in the A P is also plausible.

There is no consensus concerning the cell type containing VIP, possibly because there is plasticity o f expression. Two hormonal manipulations, i.e., estrogen and antithyroid treatment, e n h a n c e AP VIP content and influence different subpopulations o f cells to produce VIP (246,452). In hypothyroid animals VIP is localized in stellate cells different from lactotrophs and thyrotrophs (252). In hypothyroid animals, V1P m R N A is also found in stellate cells, not further identified (252,426). Others find VIP in lactotrophs (8,54,246,320,452), although, using a new VIP antiserum, Carrillo and Phelps (62) detect significant a m o u n t s o f VIP-IR cells in untreated male and female rats and indicate that these cells are not lactotrophs, even after estrogen treatment.

P E P T I D E S IN A N T E R I O R P I T U I T A R Y

549

TABLE 2 REGULATION OF PEPTIDE CONTENT AND/OR NUMBER OF PEPTIDE-CONTAINING CELLS IN AP BY PERIPHERAL HORMONES

Peptide

~ vs. 9

OVX

Ez

VIP SP, tachykinins Galanin NPY NT GRP/BBN NMB/RTN NMU Prodynorphin derived Proenkephalin A derived fl-Endorphin ACE Renin AlI IGF lnhibin Activin Vasopressin Chromogranin A Chromogranin B Secretogranin II CGRP Kinins

> > <

4' ~ 4'

4' ~ ~ 4'

>

DHT

4, 4' ~ ne

?

?

? ~' ne ?

4'

4'

?

I' ~ 4'

ORX

PTU HT TX

I' ? 1' 4'

4't ~ ne

T3 T4 (TRH)

4' ;

ADX

Dex

t ?~4'

4' 4'

R

4' ~ ne

4'

ne (4')

ne

ne Q)

~,

Age

4' ne

R, ne R R

ne 4' ~ 4'

R. ~ R R

4'

R

4' ne 4' .6, 4'

? >

?

? ~ ne ne

ne

A

R

a,R

1'

4'

a

?

A

ne I

I'

~

>

t 4' ?, A

R,

R

4' ne ne

ne,

?

4'

4'

A

ne.

The effect of hormonal manipulations and naturally occurring differences on the presence of several peptides in the AP (content of IR and/or mRNA, number of peptide-containing cells). vs. ~: compares males with females: > males contain more than females; < males contain less than females: OVX: ovariectomy; E2: treatment with estradiol or another estrogen: ORX: orchidectomy or castration; DHT: treatment with dihydrotestosterone or testosterone; PTU/HT/TX: treatment with propylthiouracil; hypothyroidism or thyroidectomy; T3/T4/(TRH): treatment with one of these hormones: effects after TRH administration are in parentheses; ADX: adrenalectomy; Dex: treatment with dexamethasone or another glucorticoid; age: effect of age, development, or puberty: I': peptide and/or mRNA increases after the manipulation; 4': peptide and/or mRNA decreases after the manipulation: ne: no effect on peptide and/or mRNA after the manipulation; *--,:separates conflicting results: underlined: only for mRNA; A: an effect is observed; R: administration of the hormone reverses the effect of organ excision. References for the data can be found in the text in the paragraph referring to each peptide.

T h e AP VIP c o n t e n t is regulated by most peripheral hormones. A low n u m b e r of VIP-IR cells is found in male rats a n d n o n e or very few in female rats (246,452). Vasoactive intestinal peptide m R N A levels are also higher in male t h a n in female rats (255). However, this sex difference is not simply related to the sex hormones, indicating that s u b p o p u l a t i o n s exist that are differently regulated. Estrogen t r e a t m e n t induces VIP-IR in female rats (246,256,452), a n d ovariectomy decreases it (354). Vasoactive intestinal peptide m R N A levels change in parallel with the peptide content after estrogen t r e a t m e n t a n d after ovariectomy (54,257,354). A n t e r i o r pituitary VIP c o n t e n t increases in hypothyroid a n i m a l s a n d decreases after T4 a d m i n i s t r a t i o n (252,255,388). In h y p o t h y r o i d i s m m R N A levels increase in parallel with the VIP c o n t e n t (54,257). These increased VIP m R N A levels in hypothyroid rats occur only in the A P (255). T h e A P VIP content a n d m R N A are u n d e r control o f glucocorticoids (54,210,257,388). Induced h y p e r p r o l a c t i n e m i a decreases A P VIP, suggesting that plasma P R L suppresses A P VIP c o n t e n t (382), a finding consistent with the localization of VIP in lactotrophs. H y p o t h a l a m i c factors m a y exert a n inhibitory tone on A P VIP expression as well because colchicine, which inhibits transport of h y p o t h a l a m i c h o r m o n e s to the portal system, enhances the n u m b e r o f VIP-IR cells (60).

Anterior pituitary cells display a basal VIP release that increases after t r e a t m e n t with K +, thyrotropin-releasing h o r m o n e (TRH), insulin-like growth factor, and growth hormone-releasing factor ( G R F ) and by hypothyroidism (52,254,388). Remarkably, at low c o n c e n t r a t i o n a d r e n o c o r t i c o t r o p i n ( A C T H ) causes an increase in A P VIP release whereas a decrease in VIP release is seen at higher c o n c e n t r a t i o n s (54). The A P expresses two types o f VIP receptors (2,499). They are located in rat lactotrophs and in h u m a n lactotropic a d e n o m a s (320,499), in the rat growth h o r m o n e (GH)- and PRL-secreting GH3 cell line (190), and in the AtT20 mouse corticotropic t u m o u r cell line (514), suggesting a role of A P VIP on P R L a n d G H release. Most research on the function of VIP has focused on the k n o w n stimulatory effect of VIP on P R L release. Vasoactive intestinal peptide is a putative hypothalamic PRL-releasing factor (304,388), a n d it was therefore a surprise to find evidence for a paracrine or autocrine function in the AP. In the reverse hemolytic plaque assay, which estimates P R L secretion from single cells, VIP antiserum reduces PRL secretion (338), thus suggesting that the lactotroph secretes VIP a n d regulates its own secretion in an autocrine fashion. This concept is strengthened by the finding that serum P R L levels increase after adrenalectomy a n d

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HOUBEN AND DENEF

TABLE 3 EFFECT O F B R A I N - G U T PEPTIDES IN AP

Effect on Hormone Release Peptide

PRL

GH

TSH

LH

FSH

VIP

t Anti-VlP: +

I'

SP/tachykinin

~ Anti-SP: ne

ne ~ ~ Anti-SP: ne

ne

Galanin

t$ ~ ne GRF ind: t, ~, ne t

ne TRH ind: t

NPY

~ ~ ne TRH ind: t Anti-Gal: ~ ~ *--,ne

ne

t, ne LHRH ind:

NT BBN/GRP/NMC

+) ~ ne ne ~ I'

+, ~ ~ ne ne

ne (I')

ne (t)

RTN/NMB

ne *--' t

ne ~ ~ ne GRF ind: ne t *--'ne

ne ne

ne ne

Anti-VlP: ~

ACTH

Other

~ *-* ne CRF ind: ~-~ ne (t)

(~)

ne AVP ind:

Other Effects

APRL stock released TRH receptor mRNA IL-6 production PRL cell line growth I' /3-endorphin

~ ~-~ n e

L and C development

~--* n e

Gastrin CCK

ne ~ ~ ne

Secretin Motilin NMU

ne

ne t *-' ne

TRH ind: Anti-NMB: f ~

t

~ t

ne

ne

ne t ~" ne CRF ind:

t Anti-CCK: ne

~-LPH /3-endorphin

t ne

Summary of data on the direct effect of peptides at AP level. Effect on hormone release and other effects are indicated in separate columns, f indicates an increase and + a decrease of the effect mentioned, and ne means that there was no effect. X ind: t, ~, or he: means that the effect induced by X is increased, decreased, or not affected by the peptide. ~-~ separates conflicting data. Anti-X: t, ~, or he: indicates whether an antiserum or antagonist against peptide X causes an increase or a decrease of the release or has no effect. Small or uncertain effects are placed in parentheses. A indicates that a change occurs after treatment with the peptide. Short statements in the column Other Effects are clarified in the text. T-label index and BrdU label index refer to incorporation experiments using [3H]thymidine or bromodeoxyuridine. Abbreviations of peptide names are as defined in the text, except for/3-endorphin (/3-End) and calcitonin (calc). References for the data can be found in the text in the paragraph concerning each peptide. are suppressed by dexamethasone in parallel with AP VIP m R N A (257). Furthermore, VIP receptor density is modified in hyperprolactinemia (318). The AP VIP-IR and plasma P R L levels also correlate after neonatal androgenization or estrogenization (503). However, basal AP VIP release decreases and basal PRL release increases by addition o f T3 to the AP in vitro (260). According to some studies, VIP can also directly affect the release of other pituitary hormones, although there is some controversy in these findings. In h u m a n A P a d e n o m a s (360) and mouse corticotropic AtT2o cells (389), VIP stimulates A C T H release, but no such effect is observed in normal rat AP cells (271,345). Vasoactive intestinal peptide, however, potentiates the effect of corticotropin-releasing factor (CRF) on A C T H release in rat AP cells according to one study (271), but not according to another (345). In normal rat AP cells V | P can also stimulate G H secretion (44). Importantly, VIP and PHI stimulate G H release from AP reaggregate cell cultures only in the presence o f a glucocorticoid and this effect on s o m a t o t r o p h s requires the presence of other cell types (21). In contrast to these data, an effect o f endogenous VIP on G H release could not be shown, as VIP antiserum had no effect on the basal G H release in dispersed AP cells from hypothyroid rats (254). It should be noted, however, that in the latter study no glucocorticoid was added to the culture system. An abstract reports that the VIP antagonist

[4-CI-D-Phe°,Leu~V]VIP, on the contrary, decreases thyrotropin (TSH) release in dispersed cells from hypothyroid animals, but has no effect on TSH release from normal AP cells (253). These data suggests a role of endogenous VIP in the feedback regulation o f TSH release by thyroid h o r m o n e . In addition to its effect on new h o r m o n e release, VIP may modulate other aspects o f cell physiology. A recent study indicates that newly synthesized PRL is preferentially released by KC1 from tissue incubated with VIP but that VIP itself as a secretagogue does not discriminate between P R L pools (285). In rat GH- and PRL-secreting GH3 cells, VIP decreases the T R H receptor m R N A level (135). Vasoactive intestinal peptide also stimulates the production ofinterleukin-6 in the pituitary (449). A stimulatory effect of VIP on cell growth was found in h u m a n PRL-secreting cell lines (383), but so far there is no evidence for a similar effect o f endogenous AP VIP.

Tachykinins Substance P (SP) was originally isolated from gut and brain as a low m o l e c u l a r weight p e p t i d e with contractile and hypotensive properties. T o g e t h e r with the related p e p t i d e s neurokinin A a n d n e u r o k i n i n B, SP belongs to the t a c h y k i n i n family.

PEPTIDES IN ANTERIOR PITUITARY

Substance P immunoreactivity has been demonstrated in AP cells by immunocytochemistry. In the rat AP the tachykininlike material has been identified as SP, neurokinin A, and neuropeptide 3' [3"-preprotachykinin(72-92) amide] by combined radioimmunoassay and HPLC analysis (47). No neurokinin B or neuropeptide K (neurokinin A precursor peptide) is detectable (47). In human AP, tachykinin-lR represents mainly authentic SP and its oxidized forms (404). Local synthesis of tachykinins in the AP is suggested by the presence of 13- and 3"-preprotachykinin mRNA (respectively coding for SP, neurokinin A and/or neuropeptide K and for SP, neurokinin A and/or neuropeptide 3') (47,207). Neurokinin B mRNA has not been detected (47). According to Morel et al. (323), SP-IR is present in rat lactotrophs and gonadotrophs and not in somatotrophs, corticotrophs, or thyrotrophs, although others demonstrate SP-IR in guinea pig thyrotrophs (104), in a subset of rat and human thyrotrophs (205,404), and in rat GH- and PRk-secreting GH3 cells (48,205). A sexual difference in the cell type containing SP-IR has been reported, suggesting plasticity in expression. In male rats, SP is found mainly in somatotrophs and also in a few thyrotrophs, whereas in females the number of SP-IR cells is lower and there are fewer somatotrophs containing SP (48). Recently, SP-IR was found in nerve fibers in the pars distalis of monkeys, dogs, and rats (48,217), where it colocalizes with calcitonin gene related peptide (156). The amount of SP-IR in the AP is regulated by most of the peripheral hormones. In rats it increases at puberty and more so in males than in females (89,106,521). Thus, SP-IR and mRNA content is higher in male than in female rat AP (47,466). Anterior pituitary SP-IR and neurokinin A-IR decrease after orchidectomy and estradiol treatment and increase after ovariectomy and dihydrotestosterone treatment (89,90,97,521). It is interesting that the effects of gonadal steroids can only be observed after sexual maturation (89,521). Substance P immunoreactivity and neurokinin A-IR in the AP increase after thyroidectomy and decrease after T4 treatment (10,89). Thyroid hormones and estrogen affect AP preprotachykinin mRNA levels in parallel with the peptide content (47,207,354). Substance P levels are also controlled by glucocorticoids. A decrease is noted after dexamethasone treatment (210) and a decrease or an increase after adrenalectomy (210). Manipulation of PRL secretion by bromocriptine and haloperidol slightly reduces SP mRNA levels, but has no effect on SP content (353). Very little is known about the release of SP from AP cells. The only information available is that there is basal release that is enhanced by K + depolarization (10,105). The AP expresses binding sites for SP and neurokinin A. They are mainly of the NK] subtype, although the existence of a small amount of the NK3 type cannot be excluded (261,300). The presence of tachykinins and their receptors in the AP, and their synthesis and release by AP cells suggest a local function in the AP. At present, however, only pharmacological effects have been reported, and attempts to demonstrate a role for the endogenous peptides have failed. In vivo SP affects the release of several AP hormones, but this probably reflects an effect at the hypothalamic level (7,82,96,98) because some of these effects could not be demonstrated on AP in vitro. In vitro exogenous SP increases the PRL release from AP (484), but has no effect on GH or TSH release (485), and increases luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion when used in very high concentrations (7,203). In rats, the effect on LH release is highest during the peripubertal period and differed between males and females (436). Neuropeptide K and neuropeptide 3" also release LH in vitro (221). In our laboratory only a marginal

551

effect of SP, neurokinin A, and neurokinin B on PRL or GH release was seen and only at very high doses (186), questioning the significance of these findings. Corticotrophs seem to be influenced by SP in two opposite ways, because SP enhances the release of/3-endorphin-IR (295) although basal ACTH release is not affected and the CRF- and vasopressin-induced ACTH release is inhibited (208,346). Others found no effect on basal or CRF-stimulated ACTH release in vitro (82). To date there are no indications for a similar effect of endogenous tachykinin peptides. The nonpeptide SP antagonist CP 96,345 failed to influence basal PRL and GH release (186). Thus, at present only speculations remain in the search for a function. A possible role may be related to tissue repair. Substance P has proliferating effects on smooth muscle cells and influences the expression of c-sis mRNA coding for plateletderived growth factor B chain (372). Endogenous SP could also be involved in a complex network between the neuroendocrine and immune system. This suggestion is based on the finding that SP has effects on the immune system (25,372), where it releases arachidonic acid metabolites, histamine, tumor necrosis factor-a, and interleukin-1. Because some of these products affect AP hormone release and are produced by the AP (see further), SP may affect AP hormone release through release of these products. Galanin Galanin, a 29 amino acid peptide, was isolated in 1983 from porcine intestine and has also been found in rat and in human AP (31,140). By means of in situ hybridization and blot hybridization, galanin mRNA was shown to be widely distributed in the rat AP (140,224). In human pituitary, the peptide is found in corticotrophs (189,491). In other species, galanin mRNA and peptide seem to be present in lactotrophs and somatotrophs, as suggested by the findings that galanin-IR colocalizes with PRL and GH in pituitary sections, that galanin mRNA can be induced in MtTW]5 PRL- and GH-secreting tumor cells, and that galanin cDNA was isolated from prolactinomas ( 133,224,355,490,491). In normal and estrogen-treated female rats, galanin expression is seen mainly in lactotrophs, with a small number of somatotrophs and thyrotrophs staining (54,188,355). In the male and ovariectomized female rat, on the contrary, galanin expression has been confined to somatotrophs and, in some studies, thyrotrophs (54,192,355). After estradiol treatment of both male and ovariectomized female rats, galanin is found in lactotrophs in both sexes, suggesting that the peptide can be present in the same cell type in males and females (192), but that sex hormones induce plasticity of expression among lactotrophs and somatotrophs. There are marked sex differences in AP galanin-IR and mRNA content, which are not seen in other tissues (140,224). The AP galanin mRNA and IR levels are higher in females than in males, vary with the estrous cycle, decrease after ovariectomy, and increase after estradiol treatment (140,224,355,492). However, another study, using a different scheme of estrogen administration, reports that estrogen treatment decreases galanin content in the rat AP (353). Castration decreases AP galanin content, but has no effect on galanin mRNA levels (355). In hypothyroid animals, galanin-IR decreases and T4 reverses this effect (180). Galanin content increases after adrenalectomy although mRNA levels are unchanged (355). Dexamethasone decreases AP galanin content and mRNA (355). The amount of galanin in the rat AP decreases in parallel with the mRNA when

552

rats are treated with haloperidol or bromocriptine (353). In vivo administration of the somatostatin analogue SMS 201-995 reduces AP galanin mRNA in estrogen-treated ovariectomized and untreated ovariectomized rats, but increases galanin peptide content in estrogen-treated ovariectomized rats. This increased content is probably due to an inhibition ofgalanin release (193). The rat AP releases galanin in basal conditions, and this release is enhanced (similar to that of V1P, which is colocalized with galanin) by low concentrations of ACTH and decreased by high concentrations of the same peptide (54). In estrogen-exposed pituitary cells, galanin release is inhibited by dopamine and somatostatin and stimulated by TRH, a finding consistent with the storage ofgalanin in lactotrophs. Growth hormone-releasing factor, luteinizing hormone-releasing hormone (LHRH), and CRF have no effect (194). However, G R F enhances and somatostatin decreases galanin release in vitro when estrogen levels are low (175), which is consistent with the finding that under low estrogen conditions galanin is stored in somatotrophs (see above). By autoradiography, no binding sites for galanin were found in the rat AP ( 191 ), indicating that, if receptors are present, their density or affinity must be low. This finding is important with respect to the search for a function. It has been suggested that galanin is an additional AP hormone because it is detectable in plasma after estradiol treatment and the AP is the only tissue showing enhanced galanin expression after estradiol treatment (224). However, local effects in the AP seem possible because administration of galanin affects pituitary hormone secretion. In vivo effects have been found (169,287,334,365), but several studies find no direct in vitro effect on GH, PRL, or TSH release (65,191,309,364,365). In other studies, high concentrations of galanin slightly stimulate LH release from AP cells of proestrous female rats (86). There are also reports indicating that high doses of galanin increase GH secretion in AP monolayer cell cultures (54,141,473) and slightly enhance GRF-induced GH release ( 191 ), whereas other studies show either no effect of galanin (365), additivity (141), or inhibition (309) of GRF-induced GH release. Some of these discrepancies may be explained by the use of rats of different ages because AP cells from younger rats respond to lower doses of galanin and because galanin inhibits GH release in older rats (473). Using reaggregate cell cultures of adult male rats, we also found a small effect galanin on GH secretion in conditions with or without estradiol. The effect was detectable at 10 nM and was maximal at 1 #M (Houben and Denef. unpublished observations). Others find a stimulation of PRL release (54) and a potentiation of the TRH-induced rise in PRL and TSH secretion (365). In our laboratory we found an effect of galanin (100-1000 nM) on PRL secretion in AP reaggregate cell cultures cultured in the presence of 1 nM estradiol. The observation that galanin receptors are undetectable in rat AP (191) correlates with the finding that only high doses of galanin provoke AP hormone release. To date, very little effort has been devoted to explore whether endogenous galanin has similar actions found with exogenous galanin. One abstract reports an in vitro study using a galanin antiserum in a reverse hemolytic plaque assay (490). This study shows that the galanin antiserum causes a decrease in basal PRL release from AP cells, and thus suggests a tonic paracrine or autocrine stimulatory action for endogenous galanin on PRL secretion.

Neuropeptide Y Neuropeptide Y (NPY) was isolated from porcine brain extracts based on its amidated C-terminus. The Y refers to its C-

HOUBEN AND DENEF

terminal tyrosine (symbol Y). Neuropeptide Y belongs to the pancreatic polypeptide family along with pancreatic polypeptide and peptide YY. Neuropeptide Y is found in the rat AP (66) and may be locally synthesized because its mRNA is present (209). According to Chabot et al., NPY-containing cells are gonadotrophs, somatotrophs, corticotrophs, and some lactotrophs, but no thyrotrophs (66). Others found NPY only in a subset ofthyrotrophs (209,354). Neuropeptide Y mRNA in the rat AP increases in hypothyroidism in parallel with VIP and SP, but is not affected by T4-induced hyperthyroidism (209). Neuropeptide Y immunoreactivity in the AP changes in parallel with the mRNA (209,354). In certain studies no NPY binding sites are found in the AP, although some direct effects of NPY on AP hormone release are detectable (51,234,472). Others do find NPY receptors in the rat AP and indicate that they are predominantly of low affinity, although some high-affinity binding sites are present as well (70,370). Neuropeptide Y, which is also present in the hypothalamus (391), affects LHRH release (222,234) and pulsatile LH release (26,305). It is suggested that NPY may have dual sites of action on LH secretion: one within the hypothalamus and another at the level of the AP gonadotroph (222). The reports concerning the direct effect of NPY on LH release are controversial. In AP cells from ovariectomized rats and in castrated bovine AP NPY has almost no effect on LH secretion (91,222), although in AP from intact rabbits NPY induces an increase in LH release in a perifusion system (234). According to some studies, NPY amplifies the LH response to LHRH (91,222). This effect on LHRHinduced LH release is contradicted by others (46,70). Other in vitro effects of NPY include a rise in GH and PRL secretion in the rat (66) and FSH in the rabbit (234), whereas TSH and /3lipotropin hormone release are not affected in the rat (66). In bovine AP cells no effect of NPY on PRL release is observed (70). Whether endogenous NPY has similar actions remains unexplored. A new light was recently shed on a possible local action of NPY by the finding that NPY, at physiological concentrations, stimulates the development of lactotrophs and corticotrophs in AP cell aggregate cultures of postnatal rats (470).

Neurotensin, Neuromedin N Neurotensin (NT) is a tridecapeptide isolated from bovine hypothalamus and intestine (477). It has a wide spectrum of actions. Rather high levels of NT-IR have been localized in the AP of several mammalian species (151). In the rat AP, NT-IR remains present after stalk transection ( 151 ), indicating that AP NT is not completely of hypothalamic origin. Recently, more evidence for local NT synthesis in the AP has been obtained by demonstrating NT mRNA in the AP (209,354). It is possible that a part o f A P NT-IR can be attributed to the related peptide neuromedin N that is encoded in the same mRNA (236). Neuromedin N immunoreactivity has been found in the cat pituitary, (59). The rat AP cells containing NT were recently identified as gonadotrophs and a few thyrotrophs; the peptide is present in the secretory granules (29). Neurotensin immunoreactivity in the rat AP is not affected by gonadectomy (151), although according to others ovariectomy increases AP NT-IR (354), and castration decreases NT-IR in gonadotrophs and increases the number of NT°IR thyrotrophs (29). Adrenalectomy (151) has no effect, but AP NT significantly decreases after thyroidectomy, TRH ( 151 ), and dexamethasone treatment (210). Neurotensin

PEPTIDES IN ANTERIOR PITUITARY

mRNA levels also decrease after TRH treatment or in hypothyroidism (209) and increase after ovariectomy (354). Anterior pituitary cells secrete NT. This release is enhanced by K + in a Ca2+-dependent way (153). Neurotensin receptors are detectable in the AP, although less than in the intermediate lobe (152). Neurotensin has no effect on basal LH, FSH, GH, or ACTH release nor on CRF-induced ACTH release (9,345,484,485). The main effects are on PRL and TSH release. In dispersed AP cells from female rats, a decrease in PRL and TSH release has been observed although the TSH response to TRH was blunted (9). In adult male AP, NT induces PRL release and this effect is additive with the effect of TRH on PRL release (9). Similarly, in hemipituitaries from ovariectomized female and normal male rats, NT increases PRL (484) and TSH (485) release. However, another study does not find such effect in AP monolayer cultures from adult male rats (134). In our laboratory, we also did not find any effect on PRL release in AP aggregate cell cultures (Schramme and Denef, unpublished observation). No studies are available exploring the putative effects of endogenous NT on secretion. The possibility that NT affects AP cell growth has been studied on human PRL-secreting cell lines, but there was no effect (383). Because NT, similar to SP, has effects on the immune system (25), a function in that area can be hypothesized. To date no experimental data supporting a role ofAP NT in immune-neuroendocrine interactions are available.

Bombesin-Like Peptides Bombesin (BBN) was first isolated from frog skin and has a wide spectrum of actions, including effects on the release of several hormones and pancreatic enzymes, smooth muscle contraction, and hypothermia. Related peptides have been discovered in mammals. The BBN-like peptides can be divided in three groups: the phyllolitorins, for which a mammalian form has not yet been isolated, the BBN-like peptides with gastrinreleasing peptide (GRP) and neuromedin (NM) C as mammalian forms, and the ranatensins with NMB, NMB-30, and NMB-32 as mammalian counterparts (461). Bombesin- and ranatensinlike-IR are present in the AP (289,314). When assayed by radioimmunoassay, NMC- and NMB-IR levels are very high in the rat AP and neurointermediate lobe compared to other brain regions (314). In guinea pig AP a substance with HPLC retention time identical to GRP is present. Gastrin-releasing peptide immunoreactivity as well as proGRP-IR remain present in AP cells after 4 weeks in reaggregate cell culture (185), suggesting that GRP-IR is locally produced in the AP. This was confirmed by a recent study showing that the rat AP expresses low levels of GRP mRNA (187). Neuromedin B mRNA could also be detected in rat AP (187,211), in human pituitary (173), and in GH3 cells (187). Earlier studies, in which less sensitive assays were used, failed to detect GRP and NMB mRNA in the pituitary (493). Gastrin-releasing peptide immunoreactivity is present in cells located in the ventrolateral part of the guinea pig AP, but the cell type was not identified (262). Neuromedin B immunoreactivity has been found in rat and mouse thyrotrophs (454) and in human gonadotrophs (445). In our laboratory, we found GRP/ BBN-IR and pro-GRP-IR mainly in a subpopulation of corticotrophs and lactotrophs, although a few gonadotrophs, thyrotrophs, and somatotrophs also seemed to be immunoreactive (185). Using other antisera, some of which possibly cross-react with NMB, Steel et al. localized BBN-IR in somatotrophs (453). Gastrin-releasing peptide/BBN and pro-GRP-IR are also detectable in the rat PRL- and GH-secreting GH3 cell line and in

553

the mouse corticotropic ART20cell line (185), strengthening the finding of GRP localization in lactotrophs and/or somatotrophs and corticotrophs. The number of GRP-IR cells decreases after propylthiouracil treatment (183) and they disappear in thyroidectomized rats (453). The number of BBN-IR cells increases after ovariectomy and decreases after estrogen treatment, although their staining intensity increases (453). However, the antisera used in the latter study poorly discriminate between GRP and NMB (453). Neuromedin B mRNA and peptide levels decrease after ovariectomy or thyroidectomy and increase after adrenalectomy or estrogen treatment (211 ). It is striking that T4 or dexamethasone have no effect on NMB mRNA levels (211), although dexamethasone treatment enhances the peptide content (211,445). The finding of specific BBN binding sites present in the rat GH- and PRL-secreting GH4C~ cell line (513) and in normal AP reaggregate cell cultures (Houben, Andries, and Denef, unpublished observations) suggests a direct action of BBN-like peptides on AP cells. The mRNAs encoding the GRP receptor and the NMB receptor were detected in fresh rat AP, although at low levels. Gastrin-releasing peptide receptor mRNA is found in GH3 cells as well (187). Direct effects of BBN-like peptides on PRL and GH release have been reported, but the data are conflicting. Several studies find no effect of GRP or BBN on PRL release from normal AP cells (32,298,331,394), whereas in rat PRL- and GH-secreting GHaCj and GH3 cells a stimulatory effect is noted on GH and/ or PRL release (41,512). A stimulatory effect of BBN on GH release is found in bovine pituitary monolayer cell cultures (32) and in dispersed ovariectomized rat AP cells (230). However, other studies fail to detect an effect of BBN on GH release at the AP level in vitro (219,331,335,394). Neuromedin B has little or no effect on GH and PRL release (184,392), although ranatensin has been shown to increase both PRL and GH secretion from GHaCj cells (512). In our laboratory we found that GRP, NMC, NMB, NMB-30, and NMB-32 can stimulate both PRL and GH release from rat AP reaggregate cell cultures. Gastrinreleasing peptide and NMC are more potent than the ranatensinlike peptides. Importantly, the GH responses are greatly enhanced by estradiol treatment of the cultures (184). The GH response to GRF in vitro is not affected by GRP, in contrast to the in vivo effect (219,229). One study finds a stimulation of LH and FSH release from rat AP quarters by high concentrations of BBN (331), but no effect on TSH release. Gastrin-releasing peptide sometimes stimulates ACTH release and can potentiate CRF-induced ACTH release in rat AP cells in a glucocorticoid-dependent way ( 120,168,361 ). Other studies deny such effect on ACTH release (500). Gastrin-releasing peptide and BBN also do not affect basal ACTH release from the mouse corticotropic AtT2o cell line (512). Attempts to demonstrate that endogenous AP GRP or NMC would exert similar effects as those found in in vitro experiments with exogenous peptides have failed: addition of potent BBN receptor antagonists failed to affect basal PRL and GH release (185). However, there is evidence for an endogenous action of NMB. Neuromedin B decreases basal (392,393,463) and TRHinduced TSH release from rat AP (392), whereas an antiserum raised against NMB elevates basal TSH release in vitro (393). Thus, because NMB is localized in thyrotrophs, it seems to be an autocrine inhibitor of TSH release. Because BBN-like peptides function as autocrine growth factors in small cell lung cell carcinomas (461), they have been tested for a similar regulatory role in the AP. However, no growth-promoting effect on human PRL-secreting tumor cell lines are found (383).

554

Gastrin and Choleo'stokinin Cholecystokinin (CCK), an intestinal peptide hormone involved in gall bladder contraction, and gastrin, a peptide that is released by the stomach and is involved in gastric secretion, show structural similarities with each other. Gastrin- and/or CCK-like peptides have been demonstrated in extracts of the AP of several species (pig, cat, rat, cow, and man) (386). Although older studies suggest that AP CCK has a hypothalamic origin (28), the presence of propeptides in AP cells suggests a local synthesis. This is supported by the finding of gastrin mRNA in whole porcine pituitaries (379) and by the detection of CCK mRNA in the mouse corticotropic ART_,0cell line (27). Although it remains uncertain whether CCK or gastrin mRNA are specifically expressed in the anterior lobe, immunoreactivity of these peptides is localized in corticotrophs [reviewed in (386)]. Rehfeld et al. have shown by HPLC and a set of selective antisera that there is a significant species difference in the presence of gastrin- and CCK-like peptides in the AP and that the processing ofpro-CCK in man and pro-gastrin in pig into active amidated CCK and gastrin seems to be inhibited (386). They find large amounts of the propeptides and only small amounts of the active peptides. The incomplete processing ofgastrin/CCK suggests that larger molecular forms present in secretory granules may be released during physiological stimulation and rapidly cleaved into the active forms (postsecretory processing) (387). Initial studies by Vijayan et al. found no in vitro effect of gastrin and CCK on GH, PRL, LH, or FSH release in rat hemipituitaries, and only gastrin decreased TSH secretion (486,487). However, later studies indicated that CCK-8 can increase PRL (290) and GH (331) secretion in vitro. Sulphated CCK, but not gastrin I, CCK-4, CCK-33, and desulphated CCK-8, stimulate ACTH release from AP sections, rat AP monolayers, and mouse corticotropic AtT:0 cells (390,415). Sulphated CCK also increases fl-lipotropin and fl-endorphin release from dispersed rat AP cells (296). Evidence for similar actions of endogenous CCK, so far, is lacking because basal ACTH release is not decreased in the presence of CCK antagonists (390). A function of gastrin and CCK in cell differentiation has been suggested because pituitary eorticotropic tumors contain carboamidated CCK in concentrations 1000 times higher than normal AP tissue (386). This also suggests that processing of precursors is disturbed in neoplastic transformation.

Secretin Secretin, a 27 amino acid peptide belonging to the secretinglucagon-VIP family, stimulates pancreatic acinar cells to release bicarbonate and water. The peptide is released principally from the duodenum. A study by Samson et al. (412) indicates that secretin is present in rat AP extracts, but further evidence for local synthesis is lacking. Secretin stimulates PRL secretion, although this observation might be due to an interaction with VIP receptors (304,412). High concentrations of secretin increase LH and FSH release from rat pituitary quarters (33 I).

Motilin Motilin, a 22 amino acid peptide found in the duodenum, regulates gastrointestinal motility. It is also present in rat pituitary and can already be detected on day 4 before birth (245). In the adult rat 80% of pituitary motilin is located in the AP (245), and in rat, guinea pig, and human AP the peptide is localized in somatotrophs (245,304,349). Local synthesis of motilin in the

HOUBEN AND DENEF AP has not been demonstrated. On the contrary, no motilin mRNA has been detected in the AP by means of a porcine gut prepromotilin cDNA probe. It was suggested that the motilinIR material detected in the brain and pituitary may be encoded by a distinct, not homologous, gene and still share amino acid homologies with the motilin sequence (349). Little is known about the function ofAP motilin. It can stimulate GH release through a direct action on AP cells (245,304), and has no effect on the release of FSH, LH, TSH, or PRL (304). The presence of motilin in the AP in an early stage of development suggests a developmental role (245).

Neuromedin U Neuromedin U (NMU), a peptide isolated from porcine spinal cord, is present in high concentrations in the AP corticotrophs (454). Recently, NMU mRNA has been detected in rat AP by Northern blot (277). Adrenalectomy, but not dexamethasone, produces changes in the morphology and number of the AP cells containing NMU, without changing the AP NMU content (454). Thyrotropin-releassing hormone treatment increases AP NMU content (111). No data are available suggesting a function of AP NMU. OPIATE PEPTIDES (TABLES2, 4, AND 5)

Prodynorphin (Proenkephalin B) Products In human AP dynorphin-IR is not detectable (165), but several reports indicate that dynorphin A-, dynorphin B-, a-neoendolphin-, and/3-neoendorphin-IR and Leu-enkephalin are present in the rat AP. In contrast to the brain, the AP contains mainly high molecular weight forms (418). No or only small amounts of dynorphin A(1-8), dynorphin A( 1- 13), and dynorphin B can be detected (95,427,460). Also, a- and/3-neoendorphin exist mainly as a common precursor (303). In this context it is interesting that the AP displays a low activity ofdynorphinconverting enzyme, which cleaves dynorphin B-29 into dynorphin B-13 (109). Prodynorphin mRNA has been demonstrated in rat [(83,95), and references cited therein] and porcine AP (377) by Northern blot hybridization experiments and in rat AP by in situ hybridization (418). The mRNA-containing cells are located in the medial region, close to the intermediate lobe (418). These data strongly support local synthesis, although other studies indicate that AP dynorphin-IR decreases by 50% after hypothalamic lesions (448). By means of immunocytochemistry, prodynorphin peptides have been localized in a subset ofgonadotrophs in rats subjected to stress and colchicine treatment. The parallel distribution of LH and dynorphin-IR after cell separation, and the fact that LHRH increases AP dynorphin release although vasopressin, TRH, CRF, somatostatin, dopamine, and T3 have no effect, indicate that also in normal AP the gonadotrophs are the likely cell type storing dynorphin [references cited in (95,417)]. The content of prodynorphin peptides in the AP varies with age, but there is no difference in the type of products present in the AP (94,429). Except for Leu-enkephalin, there is no sex difference in the AP prodynorphin-derived peptide content (429). However, a sex difference appears after gonadectomy: dynorphinIR increases after ovariectomy and decreases after castration (317), and these changes can be reversed by estradiol and dihydrotestosterone treatment, respectively (137,138). There is no parallel change in mRNA levels: dihydrotestosterone suppresses prodynorphin mRNA levels whereas treatment with estrogen has no effect (227). Thyroidectomy and adrenalectomy have no

PEPTIDES IN A N T E R I O R P I T U I T A R Y

555

TABLE 4 PRESENCE OF OPIATE PEPTIDES IN AP Cell Type Containing Peptide

Evidence for Presenceor Synthesis

Peptide Prodynorphin derived

IR mRNA Propeptides IR mRNA (P) Propeptides Remains l0 days in culture IR mRNA

Proenkephalin A derived

POMC derived

Release of Peptide by AP Cells

G

I' LHRH

Receptors for Peptide in AP Cells Opiate receptors on G

G, not S G, S, T,C T (human)

Opiate receptors on G

C FSH. LH cells T

For/3 endorphin Basal t CRF, SP. CCK, LHRH, VIP . . . . E2

Opiate receptors on G

Summary, of data on the presence of peptides in the AP. See Table 1 legend for explanation of symbols and abbreviations.

effect (317), but d y n o r p h i n - l R increases in stress and pain [references cited in (95)]. The latter finding may be related to the suppressive effect o f stress on gonadotropic function. Luteinizing hormone-releasing h o r m o n e induces the release o f d y n o r p h i n - l R . This effect is inhibited by dihydrotestosterone and d e x a m e t h a s o n e (95).

A local synthesis o f Met-enkephalin in the AP is suggested because Met-enkephalin-IR remains present in AP cells after 10 days in culture (507). There are indications that at least a part o f the AP Leu-enkephalin originates from prodynorphin, which also contains this peptide (317), but MetS-enkephalin Arg6,GlyV,Leu8, a proenkephalin A-derived enkephalin, is also found in a few cells o f the AP (444). Low a m o u n t s o f proenkephalin A m R N A have been d e m o n s t r a t e d in the whole rat pituitary (313), but no data are available for the AP. A study in male rats demonstrates enkephalins in a variable n u m b e r o f g o n a d o t r o p h s (368,443), but not in somatotrophs or /3-endorphin-containing cells. Older studies found the enkephalins in somatotrophs, thyrotrophs, corticotrophs, and gonadotrophs (475,507), but this could be due to differences in specificity and sensitivity o f the antibody and maybe to cross-reaction

Proenkephalin A Peptides Leu-enkephalin and Met-enkephalin, the proenkephalin Aprocessed peptides, are both found in the AP. Met-enkephalin, Met-enkephalin-Arg,Gly,Lys, and Met-enkephalin-Arg,Phe have been found in small amounts as authentic peptides, but the main part o f the rat AP enkephalin-IR is due to larger precursors (368). H u m a n AP, however, contains only authentic Met-enkephalin (405).

TABLE 5 EFFECT OF OPIATES AND ANF, All, AND ENDOTHELIN IN AP Effect on Hormone Release Peptide

PRL

~-Endorphin

Dopamineinhibition is blocked

Leu-enkephalin Met-enkephalin a-MSH

A ne ne t with dopamine

ANF

TSH

LH

t

t LHRH ind: Anti-/3-end: t LHRHind: t ne ne

TRH ind: ~

~ '--*ne GRF ind:

t

All

Endothelins

GH

~, ~, ne

t~lle t

t ~ ne

t ~ ne

FSH

ACTH

Other

Other Effects

LHRHind: ne Effectson cAMP, cGMP

~ ~ ne CRF ind:

t

t *~ ne

t

t ~ ne

t

t ~ ne

fl-Endorphin f

Substance P t

Summary of data on the direct effectof peptidesat AP level. See Table 3 legendfor explanation of symbolsand abbreviations.

Number ACTH secreting cells t CRF binding to previously non-CRF target cells Effectson phosphoinoside metabolism Ca2+ t in G

556

of the antisera with dynorphin or/3-endorphin (368). In human AP Met-enkephalin is present in a subpopulation ofthyrotrophs (405). Starting from day 35 of life, male rat pituitaries contain more enkephalin-IR than female rats (466,522). The AP enkephalin1R varies with the estrous cycle and in female rats enkephalinIR increases after ovariectomy although estradiol reverses this (250,522). In males enkephalin-IR decreases after castration although dihydrotestosterone reverses this effect (522). Hypothyroidism reduces AP enkephalin-IR and T3 reverses this (465). The AP enkephalin content is also regulated by the monoamine system. Effects of haloperidol (179,522), reserpine (369), and c~antagonists (369) have been demonstrated.

Pro-Opiomelanocortin Products The pro-opiomelanocortin (POMC) gene, encoding the AP hormone ACTH, is transcribed in 5-10% of the adult male rat AP cells, which are called corticotrophs, but is also expressed in the intermediate lobe. Its translation products are the hormone ACTH, the lipotrope hormones (LPH) c~-, /3-, and ~-LPH, the peptides c~-,/3-, and 3,-melanocyte-stimulatinghormone (MSH), and the c~-,/3-, and 3,-endorphins as well as the joining peptide (348,400). In the AP of adult rats, POMC is processed predominantly into the high molecular weight forms ACTH(I-39), /3LPH, and/3-endorphin (348,428), but ~-, 3'-, and/3-endorphin(19) and c~- and 3,3-MSH molecules have been detected in the AP as well (247,307,406,417,482,523). In the rat AP no 3~t-MSH is found, but in several other mammals it is detectable (3). It is remarkable that AP/3-endorphin is much less derivatized or Nacetylated than intermediate lobe/3-endorphin. As a consequence of this lack of derivatization, the AP peptide keeps its opiatelike properties (171,348,428). Also, in porcine AP, several variants of ACTH have been found (115,489), some of which have an altered biological activity (489). Due to the localization of POMC mRNA in corticotrophs, one expects to find the POMC products in corticotrophs, but ACTH-IR has also been found in FSH- and Ell-containing cells (75,330,443), as well as in thyrotrophs (81). The AP/3-endorphin content varies with age (94,428). Gonadectomy decreases AP /3-endorphin after 3-5 weeks (373). Estrogens, progestins, and testosterone can reverse the effect of gonadectomy (147,373). According to one study, propylthiouracil or T3 treatment decreases the amount of acetylated endorphin in the AP (73), whereas others found a decreased AP /3endorphin content after propylthiouracil treatment that was reversed by T3 treatment (465). Adrenalectomy increases (267) and glucocorticoids decrease AP/3-endorphin levels (18). Acute stress or single electroconvulsive shock decrease AP/3-endorphin, whereas chronic stress causes an increase (130,264). In vitro human fetal AP cells release /3-endorphin spontaneously, in a pulsatile, CaZ+-dependent rhythm independent of the hypothalamus (403). Normal AP/3-endorphin release is enhanced by CRF (18,462), SP (295), CCK (296), LHRH ( 144,231 ), VIP (118), isoproterenol (462), dopamine antagonists (D2) (121), and arachidonic acid metabolites (350), and is decreased by estradiol (231). The basal release of several POMC peptides by rat AP cells is stimulated by CRF and vasopressin (247). In mouse ART20cells, an equimolar release of the various POMC products is found (286). Somatostatin blocks stimulated release of POMC peptides from ACTH-secreting AtT2o cells, but has no effect on the release ofPOMC peptides from normal rat AP (247). To our knowledge, specific release of POMC-derived peptides from gonadotrophs or thyrotrophs has not been demonstrated.

HOUBEN AND DENEF

Function (2/AP Opiate Peptides In vivo, enkephalins afli~ctthe cell morphology of lactotrophs and gonadotrophs (319,479), and opioids influence AP hormone release (182,222,308,368,374). However, there is little evidence that these effects are due to a local action at the AP level (182,374). In vivo, opiates mainly affect LH and FSH release but PRL, GH, and ACTH release are influenced as well (374). A hypothalamic site of action is expected, but the presence of opiate receptors in the pituitary is suggestive for a local action as well (475). Some reports of direct effects of opioids on AP hormone release are available. Earlier literature data are previously reviewed (103). /3-Endorphin can stimulate TSH release and block dopamine inhibition of PRL secretion, increase LH release, and inhibit its response to LHRH (222,299). keu-enkephalin enhances the responsiveness to LHRH but inhibits TRH-induced TSH release. Leu-enkephalin also modulates PRL release (443). Met-enkephalin, on the contrary, does not modify FSH, LH, or PRL release in vitro (443). The observation that ACTH affects the release of GH, VIP, gonadotropins, and galanin from AP cells may imply a paracrine action of the classical hormone ACTH on surrounding AP cells (54,443). In vitro, c~-MSH does not alter PRL or LH release although such effects can be observed in vivo (233). Although c~-MSH has no effect on PRL release on its own in AP cell cultures from nonsuckled lactating rats, concurrent administration of c~-MSH and low-dose dopamine does stimulate PRL release, although dopamine on its own does not (176). Based on experiments with the enkephalin-derived GH-releasing peptide SK&F 110679 (GHRP-6 or His,DTrp,Ala,Trp,D-Phe,Lys-NH2), a nonopioid role for dynorphin in GH release has been suggested (85). There is one report suggesting that intrapituitary opioid peptides, possibly/3-endorphin, could exert a paracrine inhibitory action on the gonadotroph (43). This suggestion is based on the increase in LH release after treatment of AP cells with/3-endorphin antiserum, on the fact that CRF-induced LH release is blocked by the opiate receptor blocker naltrexone, and on the presence of opiate receptors on gonadotrophs (43). Because /3-endorphin//3-LPH-IR is present in peripheral plasma (506) and varies with estrous and menstrual cycles ( 164,506), pregnancy (155), season (50,131 ), and stress (371 ), a role of/3-endorphin as a hormone in peripheral opioid-responsive systems is generally accepted. An interesting hypothesis suggests that the secondary processing mechanisms, present in the pituitary, form a part of a wider pathway for the expression of nonopioid activities that are included in the /3-endorphin sequence (348). This suggestion is strengthened by the finding of the dipeptide glycyl-glutamine that can be cleaved from /3-endorphin in the AP and in other tissues (348). PEPTIDES RELATEDTO THE SALF-WATERBALANCEOR THE CARDIOVASCULAR SYSTEM (TABLES2, 5, AND 6)

Alria] Natriuretic Factor Atrial natriuretic factor (ANF), a peptide cleaved from the carboxy-terminus of a larger precursor molecule [ANF( 1- 126)], was originally isolated from atrial myocytes. Atrial natriuretic factor and its precursor are found in the rat and human AP as well (167,344). Probably at least a part of this ANF is locally synthesized because ANF mRNA is detectable in the pituitary by blot hybridization and S1 nuclease mapping [reviewed in (167)]. Atrial natriuretic factor immunoreactivity is located in gonadotrophs [references cited in (167)], although corticotrophs and lactotrophs have also been reported to contain some im-

PEPTIDES IN ANTERIOR PITUITARY

557

TABLE 6 PRESENCE OF PEPTIDES RELATED TO THE SALTWATER BALANCE OR THE CARDIOVASCULAR SYSTEM IN AP

Peptide

ANF Renin-All ACE Renin Angiotensinogen AI All Endothelins

Evidence for Presence or Synthesis

Cell Type Containing Peptide

IR mRNA

G

IR

L (human) G, endothelial cells (rat) L (human, lamb) G (rat) L (human, lamb) G, other cells (rat)

IR mRNA IR mRNA

Release of Peptide by AP Cells

Receptors for Peptide in AP

+

C, L (no mRNA)

G, C, L

By rat G t LHRH

IR IR mRNA

k (lamb) G ,-, L, C (rat) G (human)

Basal ~ IGF ~-TGF t

+ L C, T ?, not G +

Summary, of data on the presence of peptides in the AP. See Table l legend for explanation of symbols and abbreviations.

munoreactivity (325). Its mRNA is located only in gonadotrophs as assessed by in situ hybridization (322). These data suggest that only gonadotrophs produce ANF, whereas ANF found in lactotrophs and corticotrophs probably originates from internalization of circulating ANF or ANF produced by gonadotrophs (321,325). Binding sites for ANF are present in the AP (167,251,471). Based on autoradiographic studies and internalization experiments, ANF receptors are found on gonadotrophs, corticotrophs, and lactotrophs (167). The presence of ANF peptide and ANF binding sites in the AP suggests a local role of this peptide in the AP. Atrial natriuretic factor possibly decreases the cAMP production in the AP, and the ability of ANF to stimulate cGMP formation has been demonstrated in the mouse AtT2o cell line, in AP cells in culture, and in G-enriched cell populations (174,440). This suggests that ANF can modulate AP hormone release. However, a recent study indicates that the ANF effect on cGMP formation in AP cell cultures may be due mainly to proliferating nonendocrine cells (283). Several studies find no in vitro effect of ANF on basal or stimulated hormone secretion ( 167,174,410,440) and suggest a hypothalamic site of action for the observed in vivo effects (410,411). A stimulation of LH and FSH secretion in vitro has been detected, but this is probably due to a contamination of the product with LHRH ( 1). Basal and GRF-induced GH release as well as basal and CRF-induced POMC peptide release are inhibited by ANF in some studies (127,167). However, ANF has no effect on ACTH release by ART20 cells (150). A recent report from King and Baertschi (235) suggests that ANF-induced inhibition of basal and CRF-induced ACTH release requires an intact N-terminal sequence of the ANF peptide, low concentrations, and more than 1 h of incubation, The lack of an in vitro effect of ANF in previous experiments may have been due to the use of other conditions. Because the ANF gene appears to be developmentally regulated in the heart ventricles, ANF may also transiently serve a local function during development in the AP, apart from its possible action on hormone release (167).

Renin-A ngiotensin The renin-angiotensin system is known for its involvement in the regulation of sodium balance, fluid volume, and blood pressure through the release of the enzyme renin from the kidney. Renin hydrolyzes a plasma globulin to release angiotensin I, which is hydrolyzed in turn by pulmonary- and plasmaconverting enzymes into angiotensin II. The fact that angiotensin II remains present in AP organ and cell cultures and the presence of other components of the renin-angiotensin system in the AP suggest local synthesis of angiotensin II in the AP (107,142,145,146). In human pituitary and/or pituitary adenomas, renin, angiotensin-converting enzyme, and angiotensinogen are localized in lactotrophs but not in other cell types (407,409). In the lamb, angiotensinogen, renin, and angiotensin IMR are also found in lactotrophs (232). In the rat, on the contrary, most components of the renin-angiotensin system are found in gonadotrophs and some of them are found additionally in other cell types, as discussed below. In the rat minute amounts of angiotensinogen and its mRNA have been located in the pituitary [reviewed in (145,146)]. In a reverse hemolytic plaque assay, rat AP cells have been shown to release angiotensinogen (431). The cells secreting angiotensinogen consist of one cell type identified as gonadotrophs, and one unidentified, smaller cell different from the lactotrophs (431 ). After nephrectomy, on the contrary, angiotensinogen-IR has been demonstrated in a discrete number of rat AP cells that do not stain for angiotensin II,/3-LH, ACTH, TSH, GH, PRL, or S100 (145). Several studies were unable to detect the angiotensin II precursor, angiotensin I, in the rat AP (172,342). However, perifused pituitary aggregates release angiotensin I-IR, and this release is stimulated by LHRH (248). Angiotensin II-IR is localized in secretory granules of rat gonadotrophs (67,69,107,108,172,342,395,455), in corticotrophs (67), and in lactotrophs (67,455). In some cases, localization in lactotrophs could later by explained by a cross-reaction of the anti-h-PRL with rat LH (108). Anterior pituitary angiotensin IMR is authentic angiotensin II (107,395), but small amounts of angio-

558 tensin III can sometimes be detected (107). Whether angiotensin I-IR represents authentic angiotensin I, however, was not studied (248). Renin and angiotensin-convertingenzyme, necessary for the processing ofangiotensinogen into active angiotensin II, are also present in the AP. In the rat, prorenin mRNA is found in scattered cells of the AP, with a distribution consistent with that of gonadotrophs (145), whereas renin-lR was demonstrated in gonadotrophs, but not in lactotrophs, thyrotrophs, corticotrophs, or somatotrophs (107). Rat AP renin disappears after castration, reappears after testosterone treatment, and displays a more intense immunostaining in males than in females (342). Anterior pituitary angiotensin II content decreases after nephrectomy (172) but not after castration (342). In human PRL-secreting adenomas, renin is not secreted but is present in the endoplasmic reticulum, golgi apparatus, and secretory granules (407). Kallikrein, an enzyme possibly involved in the conversion of prorenin into renin (425), is present in rat lactotrophs (488). Angiotensinconverting enzyme is expressed in gonadotrophs (146,455) as well as in endothelial cells (145) and increases after ovariectomy (430). Angiotensin II receptors in the AP are located on lactotrophs and corticotrophs and on cells that probably are thyrotrophs, but not on gonadotrophs [reviewed in (145)]. Their number varies with the estrous cycle (430). The AP angiotensin receptor is of the AT~ type, which has affinity for the nonpeptide DUP753 but not for PD 123177 (430). Two new receptors for angiotensin II (AT~a and AT3) have recently been cloned from the pituitary (375,408). From these data it was suggested that AP gonadotrophs, producing angiotensin II, interact in a paracrine manner with receptors on lactotrophs and corticotrophs and affect these cells. Angiotensin II could subsequently be internalized by lactotrophs and corticotrophs (67), which could explain the presence ofangiotensin II-IR observed in these cells in some studies (67). In vitro studies have demonstrated that angiotensin II can stimulate PRL (422,456), ACTH, and /3-endorphin [( 107,143,359,501,516), and references cited therein] release, as was expected from the above data. Not expected is the observation that angiotensin II also stimulates GH, LH, and TSH release (395,397,456). Close cellular contacts are necessary for an effect of angiotensin II on GH but not on PRL release (397). Direct evidence for a paracrine action of angiotensin II on hormone secretion has been sought by means of receptor antagonists. Jones et al. (213) and Kubota et al. (248) found an inhibition of LHRH-induced PRL release by an angiotensin receptor antagonist when high doses of LHRH were used. However, studies in our laboratory, using more physiological doses of LH RH (1-10 riM), detected no effect of angiotensin receptor blockers (395,396). Thus, although several data suggest that an intrapituitary renin-angiotensin II system may be involved in the regulation of AP hormone release, conclusive experimental evidence for such a role is lacking. Besides its effects on hormone release, angiotensin II increases the number of ACTH-secreting cells and may promote the binding of CRF to previously non-CRF target cells [reviewed in (423)]. Endothelins Endothelins are peptides with vasoconstrictive and pressor activities isolated from endothelial cells. Endothelin-1 and endothelin-3 are abundantly present in the rat AP (110) and both are found in human pituitaries as well as their mRNAs (464). In human pituitary endothelin-3-IR is localized in gonadotrophs

HOUBEN AND DENEF but not in corticotrophs, thyrotrophs, somatotrophs, lactotrophs, or folliculo-stellate cells (343). Receptors are also found and are probably of the ETA type (181,274,464). Endothelin-1 and endothelin-3 are released by AP cells (294). Insulin-like growth factor I and II increase endothelin-3 release whereas TGF-/3 enhances endothelin-I release and reduces endothelin-3 release (294). Endothelins affect the phosphoinositide metabolism in AP cells, rat GH- and PRL-secreting GH3 cells, and c~T-3 gonadotropic cells (274), and endothelin-1 was also shown to enhance cytoplasmic Ca 2+ in single gonadotrophs (457). Endothelin-2 and -3 stimulate or inhibit PRL release depending on the presence of serum, the concentration of the endothelin, and the duration of the stimulus [( 110,113,274,414), and references cited therein]. According to some groups, endothelin-I is ineffective on the release of PRL ( 113,414). Endothelins have no effect on the release of other AP hormones according to some studies, but stimulate LH, FSH, GH, and TSH release according to others [reviewed in (110,113,424)]. Part of these controversies are due to the use of static incubation systems on the one hand and perifusion systems, detecting transient stimuli, on the other (274). Endothelin-I releases SP from AP [reviewed in (113)]. G R O W T H FACTORS (TABLES 2, 7, AND 8)

Basic and Acidic kTbroblast Growth Factor Fibroblast growth factor (FGF), which was discovered in brain and pituitary extracts, was first recognized by its mitogenic effect on 3T3 fibroblast cells, but stimulates the division of a wide variety of other cells types as well. Basic (b)-FGF and acidic (a)FGF are closely related peptides, binding on the same receptor, having similar effects, but encoded by different genes (162). In the pituitary, high amounts ofb-FGF-IR and little or no a-FGFIR have been demonstrated (126,159,161,178,380). The finding of b-FGF mRNA in bovine pituitary cells suggests local synthesis in the AP (126). Cultured monolayers of bovine pituitary folliculo-stellate cells contain b-FGF peptide and mRNA, indicating that folliculostellate cells are an intrapituitary source of b-FGF (126). This is consistent with the observation that bovine pars tuberalis, being rich in nonhormone-secreting cells, contains much more FGF than the pars distalis (126). Recently, however, a majority of bovine pituitary endocrine cells was shown to contain b-FGF (510), and in Fischer 344 rats gonadotrophs contain b-FGF (419). Preliminary studies suggest that b-FGF is present in a subset of rat corticotrophs not responding to adrenalectomy (22). The genes for b- and a-FGF do not code for a signal peptide and accordingly, locally produced FGFs are sequestered in the cell of origin. Thus, the peptide may be involved in intracrine effects, in extracellular matrix synthesis, or in events like wound healing, tissue remodeling, or neoplasia ( 124,161). Alternatively, b-FGF could be secreted from cells in association with the extracellular matrix component heparan sulphate, and subsequently liberated by hydrolysis of the matrix (124). Some effects of FGF, observed after in vitro addition of this growth factor to AP cells, may correspond to effects of endogenous peptides homologous to FGF such as the recently isolated members of the FGF family FGF-5, FGF-6, KGF hst/KS3, some of which can be secreted [references cited in (244)]. However, bovine AP releases FGF to a small extent. This release increases after KCI administration (22). The effect of KC1 on FGF release was significantly enhanced in the presence of estradiol, but estradiol by its own has no effect on FGF release (22). In normal rat AP, on the contrary, KCI does not induce FGF release in detectable amounts (22).

PEPTIDES IN A N T E R I O R P I T U I T A R Y

559

TABLE 7 PRESENCE OF G R O W T H FACTORS IN AP

Peptide

Evidence for Presence or Synthesis

FGF

IR mRNA

EGF/c~-TGF

IR mRNA

IGF l

IGF It VEGF /3-TGF

IR mRNA IR mRNA mRNA Peptide isolation IR mRNA

Cell Type Containing Peptide

Release of Peptide by AP Cells

FS, endocrine cells (bovine) C (rat) G (rat) L, not C, T or G (bovine) L, S (bovine) T, G (human) FS-like (rat) S (bovine, GH3)

Basal KCI

FS (bovine) FS, other cells

+ (bovine)

Receptors for Peptide in AP

Basal

+ L,S

Basal ~' T3 (F4Z2) Dex (F4Z2)

+

+

G, other cells GH3, GC + S, other cells + GH3

Summary of data on the presence of peptides in the AP. See Table 1 for explanation of symbols and abbreviations.

In the rat PRL- and GH-secreting GH4 cell line and in M t T / S cells, F G F decreases G H release ( 162,198). Basic-FGF enhances PRL release from human AP adenomas after 3 days to 4 weeks of exposure (13) and in GH4 cells it increases PRL secretion after 3 days of incubation (22,162). This effect is potentiated by estradiol in normal cells as well as in the rat PRL- and G H secreting GH3 cell line (22). After 24- or 48-h preincubation of rat AP cell cultures with FGF, the sensitivity of the cells to T R H induced PRL and TSH release is increased, although the response to CRF, GRF, and L H R H is not modified (22). Basal PRL release rises and basal TSH release is not affected (22). The number of cells increases after 48 h of F G F treatment, but the effects on PRL and TSH release remain present after addition of 5-fluorodeoxyuridine, which blocks the effect of F G F on the cell number (23). Thus, the effect of F G F on PRL and TSH release is not due to a proliferation oflactotrophs and thyrotrophs. After 4-h incubation of AP cell cultures with F G F no effect on cell number or on basal or stimulated PRL, GH, LH, FSH, A C T H , or TSH release is observed (23). However, acute effects (30-240 min) of F G F have recently been demonstrated by means of a reverse hemolytic plaque assay. The growth factor reduces PRL secretion, blocks TRH-induced PRL secretion, but does not affect the inhibitory effect of dopamine on PRL secretion (263). Thus, b - F G F seems to have a biphasic effect on PRL release: a stimulatory effect is seen with low doses and long incubation time, and an acute inhibitory effect is seen with higher doses (510). Some of these effects of b - F G F may be explained by effects at transcriptional level because in the rat PRL- and GH-secreting GH3 cell line b-FGF enhances the m R N A of Pit- 1, a transcription factor for PRL and G H (53). Another study indicates that bF G F increases PRL m R N A in GH3 cells (42). It has no effect on G H m R N A levels in rat pituitary monolayer cultures or GH3 cells (42,519). Several data indicate an effect of F G F on cell proliferation, although this effect can be stimulatory or inhibitory. Basic-FGF increases the [3H]thymidine labeling index in rat AP cell cultures (23,306) and ovine pituitary cell cultures (447). It stimulates GH3 cell proliferation [reviewed in (510)], but according to other

studies F G F decreases GH4Ct and M t T / S cell proliferation (198,383). Recombinant F G F has been shown to inhibit cell growth in two human PRL-secreting tumor cell lines (383). There is also a suggestion that F G F may be involved in the development of estrogen-dependent pituitary tumors (22). Several human pituitary tumors contain less F G F - I R than normal AP. Because F G F inhibits the growth of human pituitary tumor cells, reduced F G F levels may favor pituitary tumor growth (439). Fibroblast growth factor may also affect the differentiation of AP cells because in ovine pituitary cell cultures, cultured in the presence of b-FGF, null cells predominate (447). In vitro, b - F G F affects the morphology of the pituitary somatotroph-like cell line MtT/S and of normal dispersed pituitary cells (198). The effects are detectable after 12 h and are possibly induced by F G F adhering to the culture dish. The difference between control and F G F treatment in normal AP cells disappears after 48 h, probably because AP cells produce b-FGF. Previous observations have suggested that the pituitary is not a source for F G F delivery to other tissues (23). The presence of this angiogenic factor in folliculo-stellate cells of the pars distalis may be related to the development and maintenance of the differentiated state of the portal vessels ( 126,161 ). Pituitary FGF, present in gonadotrophs, may also be involved in the different response to estradiol between Fischer 344 and Sprague-Dawley rats, as suggested by Schechter and Weiner (419).

Transforming Growth Factor-c~ and Epidermal Growth Factor Epidermal growth factor (EGF) was isolated from extracts of mouse salivary gland. It influences the differentiation of specialized cells in early life and stimulates mitogenesis, mainly in cells of ectodermal origin and in some mesodermal cell types. Transforming growth factor-c~ (c~-TGF) is structurally homologous to E G F and binds to the same receptor (129,510). Cultured cells from bovine AP secrete EGF-like peptides (249), one of which was identified as a - T G F (242). Recently, aT G F m R N A has been demonstrated in bovine AP (333). The c~-TGF m R N A levels increase when the cultures are allowed to incubate in their own conditioned medium, when they are treated

560

HOUBEN AND DENEF

TABLE 8 EFFECTS OF G R O W T H FACTORS IN AP Effect on Hormone Release Pepfide

PRL

GH

TStt

FGF

~, ~, ne TRH ind: t, {

+

ne TRH ind: t

EGF/c~-TGF

t '--* ne

t

ne

IGF I/IGF |I

{ *~ $ ~-~ ne

t$ GRF ind:

LH

FSH

t

~' ~ ne

VEGF 6-TGF

ACTH

t ~ ne

t '--+ne

Other Effects

Other

Endothelin-3:

Cell number t ~ Pit-I mRNA f PRL mRNA Cell differentiation Cell morphology PRL synthesis and mRNA GH synthesis t, mRNA ne cell proliferation, cell morphology, adhesion Dopamine receptors on OH3 t T-label index ~ ~-+ Brdu label index ne ACTH/POMC cells t' GH mRNA GH3 cell growth enhances L differentiation PRL production and mRNA t~-TGF expression Cell proliferation E2-induced L proliferation T-label index ~ (in presence of E2)

Summary of data on the direct effect of peptides at AP level. See Table 3 legend for explanation of symbols and abbreviations.

with phorbol ester, or with E G F (333). In normal bovine AP cells c~-TGF-IR has been localized by immunocytochemistry (242). Some of these cells are lactotrophs but there are no c~TGF-containing corticotrophs, thyrotrophs, or gonadotrophs whereas somatotrophs were not tested (242). Another study indicates the presence of a - T G F in somatotrophs and lactotrophs (332). In human pituitary EGF-IR has been localized in thyrotrophs and gonadotrophs identified by electron microscopy (242,510). The E G F receptor and its m R N A were also detected in the AP (333,510). Phorbol ester increases the E G F receptor m R N A level although EGF itself has no effect (333). In the rat, EGF binding sites are present mainly on lactotrophs and somatotrophs as identified by electron microscopy (510). The presence of EGF receptors and ligands in the AP suggests that AP a - T G F may have a short range action within the AP. Acute treatment of the rat PRL- and GH-secreting GH4CI cell line with EGF increases PRL release (421 ) but in normal rat AP cells it provokes a release of G H without affecting PRL or TSH secretion (129,333,510). Others have shown that high concentrations of E G F stimulate LH release from normal rat AP ( 129,510). Lower doses of E G F do not affect basal and L H R H induced LH release, but the effect ofestradiol on the LH release is stimulated (5 I0). Childs et al. (79) indicate that E G F stimulates A C T H release in AP cultures, although an older study did not

observe such effect [reviewed in (453)]. This effect on A C T H release suggests that EGF receptors are present in corticotrophs or that paracrine interactions occur between EGF receptor-containing cells and corticotrophs. Epidermal growth factor also increases the number of A C T H - I R - and P O M C m R N A - c o n taining cells in culture (79). Epidermal growth factor has been shown to inhibit G H and stimulate P R L synthesis in the GH4Cj rat pituitary cell line after chronic t r e a t m e n t (333,421). The effect on PRL synthesis appears to be regulated at the transcriptional level, because addition of E G F to GH4 cells increases the expression of the P R L gene and increases P R L m R N A levels (510). However, E G F does not affect G H m R N A levels in rat pituitary m o n o l a y e r cell cultures (519). Apart from these effects on hormone release and synthesis, AP E G F or c~-TGF affect AP cell growth or differentiation. Transforming growth factor-c~ inhibits GH4CI cell proliferation (384,421 ), causes morphological changes (421,510), and increases GH4CI cell adhesion (384). Treatment of the rat G H - and PRLsecreting cell line GH3 with E G F during 4 days causes morphological changes and induces the expression ofdopamine receptors in this cell line, suggesting that E G F affects gene expression leading to differentiation of GH3 cells into L-like cells (315). However, EGF has no effect on bromodeoxyuridine labeling index in normal rat AP cells (306). Added together with estrogens, it enhances

PEPTIDES IN ANTERIOR PITUITARY

[3H]thymidine uptake in ovine pituitary cell cultures and, like FGF, it increases the number of null cells (447).

Insulin-Like Growth Factor I and II Insulin-like growth factors (IGFs) are polypeptides mediating the growth-promoting effects of GH (92,510). Insulin-likegrowth factor I-IR is present in bovine AP (351), and its mRNA has been found in GH3 cells and in normal rat AP (119,280,511). Relatively high concentrations o f l G F II-IR are found in human and rat AP (92,270). Insulin-likegrowth factor II mRNA is present in the developing pituitary of embryonic rats (459), but low levels of IGF II mRNA are present in adult rat AP as well (20). This is consistent with the finding that IGF II mRNA is usually highest during fetal development and decreases in the postnatal period (92). By in situ hybridization, IGF I mRNA is found in scattered cells in the rat AP, ressembling folliculo-stellate cells (20). On the contrary, 1GF I-IR was localized in bovine somatotrophs (351) and in GH3 cells that secrete the peptide as well (119). Insulin-likegrowth factor 1 mRNA decreases in rat PRL- and GH-secreting GH3 cells cultured in thyroid hormone-depleted medium, but increases again after subsequent treatment with T3 or GH (119). After estrogen treatment IGF I mRNA increases (312). Rat AP releases an IGF-like peptide of unknown nature (37). This release is strongly inhibited by cycloheximide, suggesting that the peptide is synthesized in the AP (37). In the F4Z2 cell line, originating from the MtTF4 rat pituitary tumor, IGF I release increases in the presence ofT3 and decreases in the presence of dexamethasone (524). Insulin-like growth factor receptors have been demonstrated in rat AP membranes (158), cultures (401), and GC and GH3 pituitary tumor cells (518). Their number decreases after thyroidectomy without a change in the affinity (297,510). Receptors for IGF II are found in the embryonic AP and remain present in the adult rat (478), but the IGF 1 receptor and its mRNA are present as well (20,401). In rat AP, IGF I receptor mRNA is homogenously distributed (20). It is probably present in endocrine cells, and there is an overlap, but no particular correlation, between GH cells and IGF I receptor mRNA-containing cells (20). The IGF II receptor is the most abundant in the rat AP (401 ). Although it is present on most somatotrophs, and also on other AP cells (352), the effect oflGF II on GH release is probably mediated through IGF I receptors (508). In vivo, the majority of IGF is bound to specific IGF-binding proteins (442). mRNAs for several of these binding proteins are present in rat AP tissue and show distinct patterns of localization (20). Some studies indicate that media from AP cell cultures and rat GH3 cells contain such IGF-binding proteins (37,64,259,402), and that their production is regulated by IGF, estradiol, and T3 (64,312,442). Several groups have found direct effects of IGFs on GH and PRL production and/or release by AP cells. Low concentrations of 1GF I stimulate the GH release from rat AP cells (maximum effect 1 #g/l), and high concentrations decrease GH release (ICs0 20 ~tg/1) (442). On the contrary, IGF II does not stimulate GH release at lower concentrations (442). In rat pituitary cultures, IGF I and/or IGF II inhibit (Bu)2cAMP-, T3-, or theophyllineinduced GH release (157,297,508) and both IGFs inhibit basal and GRF-induced GH release in chronic tests (3-24 h) (157,508). A more acute effect of IGF I and, to a lesser extent, of IGF II on GRF-induced GH release has also been reported [reviewed in (510)]. The effect of IGF 1 on GH release is abolished by pretreatment with dexamethasone (258). Apart from its effect

561

on the GH secretion, IGF I also reduces basal, GRF-, and T3stimulated GH mRNA levels (297,341,519). As far as PRL release is concerned, the results are less uniform. An inhibition of PRL secretion by IGF I has been shown in rat and human pituitary explant cultures (157) and in AP cell cultures (258), but other studies have found no effect of the growth factor on stimulated PRL secretion (157) or PRL gene transcription (519), or even an increased release and rise of PRL content (52,258). From these observations, a role for serum IGF in the longloop negative feedback (158) or for AP IGF in the short-loop negative feedback (119) of GH and/or PRL secretion has been suggested. This hypothesis is strengthened by the finding that in most human somatotropinomas IGF-II does not cause a decrease in GH release. Thus, somatotropinomas may be autonomous tumors that are no longer subject to normal GH regulation by IGFs (170). Recently, IGF I has been shown to increase the release of LH and FSH and to decrease the cellular content of these hormones (223), but older studies deny such effect [(157), and references cited therein]. To date no effects on ACTH secretion (157) have been found. Certain studies indicate that IGFs induce the release of pituitary peptides. Both IGF I and II enhance the release of endothelin-3 by AP cells in culture (294). A recent abstract reports that IGF I releases PRL and VIP, and that the effect of IGF I on PRL release is abolished by VIP antiserum (52). This suggests that VIP mediates the IGF effect on PRL release. Little is known about the effect of IGF on AP cell growth, but in serum-free culture medium, GH3 cell growth is slightly enhanced by IGF I [reviewed in (510)]. An interesting finding is that IGF-I induces differentiation of lactotrophs in the GHsecreting MtT/S cell line (197).

Vascular Endothelial Growth Factor Recently, Ferrara and Henzel (124) and Gospodarowicz and Lau (163) isolated vascular endothelial growth factor (VEGF), a novel heparin-binding growth factor, specific for vascular endothelial cells, from media conditioned by bovine pituitary folliculo-stellate cells. The growth-promoting effects of VEGF are limited to a more narrow spectrum of cells than the effect of FGF (160). Vascular endothelial growth factor mRNA has been found in 20% of the normal AP cells, suggesting that cells other than folliculo-stellate cells, which account for only 5-10% of the AP cells, can express VEGF (125). Its presence in folliculo-stellate cells suggests a role in the microvasculature of the AP, although other functions are possible as well (125). Its binding to the AP has been shown but may be associated with vascular endothelial cells (125).

Tran~'lbrming Growth Factor-c3 Transforming growth factor-/3 (/3-TGF) belongs to the inhibin/ activin family of growth factors and ¢3~-TGF-IR is present in extracts from AP and AP cell cultures (416). Because ¢3j-TGF mRNA is detected in AP and AP cell cultures by Northern blot hybridization, this growth factor can be produced in the AP (416). Transforming growth factor-/3 is secreted by AP cell cultures enriched in lactotrophs (416). Receptors for fl-TGF have been demonstrated on the rat GH- and PRL-secreting GH3 cell line (72). It suppresses basal and estradiol-induced PRL release from rat AP cell cultures enriched in lactotrophs (after 4 h addition) (416). This can be related to the fact that/3-TGF inhibits PRL production in GHaC~ cells (384) and reduces PRL mRNA levels

562

HOUBEN AND DENEF TABLE 9 PRESENCE OF GONADAL PEPTIDES IN AP

Peptide

Inhibin

Activin

Follistatin

Cell Type Containing Peptide

Evidence for Presence or Synthesis

IR: ~,/3B mRNA c~, ~B(rat) /3B,flA (monkey) IR: fib mRNA ¢3B(rat) /3B,flA (monkey) Peptide isolation mRNA

Release of Peptide by AP Cells

Receptors tbr Peptide in AP

G

+ GH3

G

GH3 AtT20

FS, G, S, L, T

+

Summary of data on the presence of peptides in the AP. See Table 1 legend for explanation of symbols and abbreviations.

in GH3 cells without affecting Pit- 1 mRNA (102). It also inhibits a-TGF expression in bovine AP cells in culture (332). Transforming growth factor-fl inhibits GH4C~ cell proliferation (384) and reduces the proliferation of bovine AP cells in culture (332). In ovine AP cells, f - T G F together with estradiol stimulates [3H]thymidine uptake (447). On the contrary, f - T G F inhibits estradiol-induced lactotroph cell proliferation in rat AP cell cultures (416). Interleukins Interleukins (ILs) are polypeptides produced by lymphocytes or macrophages and involved in immunological responses. The insight that there are interactions between the immunological and the neuroendocrine system has led to the search for ILs in the AP. Interleukin-6 immunoreactivity and/or mRNA have been found in rat and mouse AP (481) and in several human pituitary adenomas (215,483). In the mouse, IL-6 is present in folliculostellate cells as shown by double immunostaining with S100 antiserum (481). Interleukin-6 is also localized in GH and ACTH cells in human tumors (483). Its production in AP cells is regulated by VIP, pituitary adenylate cyclase activating peptide (PACAP), dexamethasone, and calcitonin gene-related peptide (449,467). Interleukin-6 is released by folliculo-stellate cells (56) and by some pituitary adenomas (228). Interleukin-6 receptors and their mRNA have been found in rat and human AP cells (356). In human AP, IL-6 receptors were found on gonadotrophs (other cell types were not yet studied) (356), but its receptor mRNA is present in gonadotrophs and corticotrophs in human tumors (483). Interleukin-6 stimulates PRL, GH, ACTH, FSH, and LH release, modulates TRH and dopamine effects on PRL, and affects GH release by GRF [for reviews see (228,424)]. In another study, no effect on AP hormone release was seen after l-h incubation of rat hemipituitaries with IL-6 (284). After 2 h, however, ACTH and GH release are increased (284). After longer exposure times, IL-6 slightly inhibits CRF-induced ACTH release (480). Interleukin-6 stimulates the release and synthesis of ACTH in mouse corticotropic AtT20 cells (136). In GH3 cells, IL-6 stimulates [3H]thymidine incorporation but it has no effect on normal rat AP cell growth (11). Interleukin-lf mRNA is present in AP cells and IL-lf-IR is localized in thyrotrophs (243). Receptors for IL-1 have been

detected on pituitary cells (228). In mouse corticotropic AtT2o cells, treatment with CRF for 24 h increases the density of ILl binding sites without changing their affinity (509). lnterleukin-I has been shown to enhance LH, GH, and TSH release (228,420). Basal, VIP-, and TRH-stimulated PRL secretion and production are inhibited by IL-1 in vitro (228,420). It also enhances POMC gene expression (136,228), causes ACTH release in normal pituitary cell cultures, and enhances basal ACTH release as well as the ACTH response to CRF, VIP, and phorbol esters in AtT2o cell cultures (228,509). Because IL-1 stimulates IL-6 release from AP cells, some of its actions may be mediated by IL-6 (215,450,451,476). Interleukin-2 mRNA is present in human corticotropic adenoma cells and in mouse corticotropic ART20cells (12). Interleukin-2 receptors are found on GH3 cells and on corticotrophs, lactotrophs, and somatotrophs in rat AP (11,12). Interleukin-2 stimulates [3H]thymidine incorporation in GH3 cells but has no effect on normal rat AP cell growth (11). GONADAL PEPTIDES (TABLES 2. 9, AND 10)

lnhibin and Activin Inhibin and activin are two dimeric glycoprotein hormones exerting, respectively, a negative and positive feedback on FSH secretion (101,520). Together with Mullerian inhibiting factor and f - T G F they belong to a large peptide family (101). Inhibin consists of one c~ and one/3 subunit whereas activin consists of two 13subunits identical to those present in inhibin (101). Two variants of the/3 subunit, called fA and fB, have been identified (101,520). Thus, for inhibin one distinguishes inhibin A (C~fA) and inhibin B (c~flB) and for activin there is activin A (/3AfA), activin B (fBflB), and activin AB (fAfB). The mRNAs of the c~ and fB chain have been detected in normal rat AP (398). The fA chain mRNA could not be detected (310), although the peptide fA chain is detectable in cell nuclei (398). These data suggest that rat AP cells produce preferentially inhibin B and activin B, which is in contrast to the main finding ofactivin A and AB in other tissues (293). In monkey pituitary, inhibin fn mRNA is present although fA mRNA is found in some samples and c~ mRNA is not detectable (16). The c~ and fib chains have been localized by immunocytochemistry in the cytoplasm of 90-100% of the rat AP gonadotrophs, but are absent in other AP cells (398,399). The fA subunit has a nuclear localization and is found all over the AP and the

PEPTIDES IN A N T E R I O R P I T U I T A R Y

563

TABLE 10 EFFECTS OF GONADAL PEPTIDES IN AP Effect on Hormone Release Peptide

PRL

GH

lnhihin

TSH

LH

FStt

ACTH

(~,) LHRH ind:

Activin

TRH ind: ~

¢

ne ~ I'

~ LHRH ind: I' Anti-activin B:

Follistatin

~ ART20 ne

Other

Other Effects LHRH receptors + *--, FSH-/3 mRNA ~ (LH-/3 mRNA ~) LH, FSH content FSH content, mRNA, cell number LH-c~ and -/3 mRNA I' POMC mRNA GH synthesis, mRNA Pit-I binding to GH promoter GRF induced S proliferation LHRH receptor synthesis GH4CI proliferation ~, PRL production +, adhesion AtT20 proliferation ~, POMC mRNA +, release FSH content, synthesis, mRNA LHRH binding sites Binds activin

Summary of data on the direct effect of peptides at AP level. See Table 3 legend for explanation of symbols and abbreviations.

neurointermediate lobe (398). The significance of the latter finding is unclear. Ovariectomy causes an increase in the a and ~B m R N A levels in rat AP and an increase in the size and number of a and [3B chain containing cells that is prevented by estradiol (398). The ¢/A chain-IR is not affected by ovariectomy or by estradiol (310). Receptors for inhibin were found in the rat AP (132,202). In the rat PRL- and GH-secreting GH3 cell line a ~ - T G F receptor is present that also binds activins and inhibins (72). Activin binding sites are found on mouse corticotropic AtT20 cells (34). Because the gonads are acknowledged as the predominant source of circulating inhibin-related peptides, it seems unlikely that the pituitary contributes significantly to plasma inhibin levels (398). The possibility exists that AP inhibin and activin have a local function. Inhibin and activin have well-known effects on FSH secretion in vitro. These effects are observed after chronic treatment whereas short-term treatment has no effect. Inhibin inhibits basal and LHRH-stimulated FSH release (55,122,123,202,240). Effects on LH release by higher concentrations of inhibin have been reported in some studies (55,122,123,202,266,336,337,520). The kinetics and magnitude of the action ofinhibin on FSH and LH release differ depending on the presence or absence of L H R H and the mode of L H R H stimulation (201). An interaction of inhibin and androgens on L H R H - i n d u c e d FSH release has been found (55,202,240). In rat pituitary, inhibin inhibits L H R H - i n d u c e d L H R H receptor upregulation (497) and reduces the number of L H R H binding sites (497), but it does not compete for L H R H binding sites (497). Others, however, report an increase in the number of L H R H binding sites by inhibin in ovine pituitary culture (266). Some of these influences on the L H R H binding sites may explain the effects of inhibin on gonadotropin secretion in response to L H R H , but other groups suggest that those effects are due to a reduction of FSH and LH production by inhibin. Arguments for the latter interpretation are the inhibitory effect of inhibin on FSH-/3 (15,57,84,202) and (in certain circumstances) LH-13 m R N A levels (14), the parallel effect of inhibin and cy-

clohexemide on FSH and LH secretion (200), and the decrease in AP FSH and LH content by inhibin (122). Recent evidence suggests that the effect of inhibin on the response to L H R H is due to an action beyond the L H R H receptor, e.g., at the level of protein kinase C or Ca2+/calmodulin (496) Activin A, B, and AB stimulate basal and L H R H - i n d u c e d FSH release in vitro. This effect is detectable after 6 h and maximal after 24-72 h of treatment (17,88,237,520). The stimulatory effect of activin A on FSH release is potentiated by SRIF and low cell densities (238). To date most reports find no effect on LH release (226,237) or find only a small increase (20-30% after 24 h) (17). In sheep pituitary, activin A suppresses L H R H - i n duced LH release (337). Activin A increases the FSH content and the number of FSHIR cells in the AP (226,337,520). In different cell populations separated by centrifugal elutriation, activin A increases the number of FSH cells in a middle-sized cell fraction whereas it stimulates FSH secretion from larger FSH cells without affecting the cell number in the larger cell fraction (225). However, the effect of activin A on FSH release may also relate to its ability to stimulate L H R H receptor synthesis in rat AP cell cultures or to its effect on FSH m R N A . Activin A increases FSH-3 m R N A in concert with FSH secretion in cultured pituitary cells (after 4 h) [reviewed in (17,57,148)]. The effect of activin A on FSH/3 m R N A levels is at least in part due to an increased stability of FSH-/3 m R N A in the presence of activin A (58). Activin A also causes a small increase in I_H-/3 and -c~ m R N A (after 2 h) (17). There is good evidence that activin B, present in gonadotrophs, has an autocrine role in the AP (88). Incubation of AP monolayers with a monoclonal antibody against activin B reduces basal FSH secretion in a time- and concentration-dependent way (88). Follicle-stimulating hormone-13 m R N A levels are reduced by the antibody as well, but there is no effect on LH-¢3 or -c~ m R N A levels, on basal LH release, or on LHRH-stimulated LH or FSH secretion (88). An antibody against inhibin-~ has no effect on basal FSH secretion (88). Beacuse activin B by itself

564

HOUBEN AND DENEF

TABLE 11 PRESENCE OF POSTERIOR LOBE AND HYPOTHALAMIC PEPTIDES IN AP Peptide

Evidence for Presence or Synthesis

Vasopressin

IR mRNA

Oxytocin

IR mRNA

Neurophysin Somatostatin GRF

LHRH

TRH

CRF

IR mRNA IR mRNA (adenomas) Remains 7 days in culture IR mRNA Remains 21 days in culture IR Propeptide Remains 21 days in culture IR

Cell Type Containing Peptide C, At-l'20 L. G, T not S

C, AtT20 T. L, S. not C, G Fibers S (monkey) FS (teleosts)

Release of Peptide by AP Cells +

Receptorsfor Peptide in AP + C, (G) C.T 4 G, (C)

Adenomas +

G

L, C T

+

G. L, C C

Summary of data on the presence of peptides in the AP. See Table 1 legend for explanation of symbols and abbreviations.

stimulates FSH secretion and because activin B can be produced by AP gonadotrophs, these findings suggest that the AP gonadotroph differentially modulates the secretion of LH and FSH in an autocrine way through activin B (88,31 l). Some effects ofactivin A on GH, PRL, and A C T H release, on biosynthesis, and on cell proliferation were reported (33,237,311). Activin A inhibits TRH-induced PRL release (237,311). After long exposure, activin A inhibits basal and stimulated G H release from human GH-secreting adenomas (239) and in rat AP cell cultures (35,237). Activin A also inhibits basal G H biosynthesis (detectable after 24 h) as well as GRF-, glucocorticoid- and thyroid hormone-stimulated G H biosynthesis (36). In MtTW15 somatotropic tumor cells, activin A decreases G H m R N A levels, probably because it inhibits binding of the transcription factor Pit-I to the G H promotor (458). Activin A inhibits the growth-promoting effect of G R F on a purified population of normal AP somatotrophs, but has no effect on basal proliferation of somatotrophs (36). Activin A inhibits cell proliferation and PRL production in the rat PRL- and GHsecreting GH4C~ cell line and enhances cell adhesion (384). In AtT20 cells, activin A suppresses the proliferation and reduces basal A C T H secretion and P O M C m R N A levels after prolonged exposure (34), but this is not seen in normal pituitary corticotrophs (398,424). Follistatin Follistatins, novel single-chain glycosylated polypeptides, were isolated from porcine and bovine ovarian follicular fluid (311) based on their ability to inhibit FSH secretion (520) and FSH3 m R N A levels in rat pituitary cell cultures (57), similar to inhibins. Recently, follistatins were detected in bovine pituitary and in medium conditioned by bovine pituitary-derived folliculostellate cells that also contains V E G F (311). This suggests that the AP folliculo-stellate cells are capable of producing and secreting follistatins. Follistatin m R N A has been detected in whole rat pituitaries by hybridization followed by RNAse protection

assay and PCR (220). In diestrous rats, follistatin is found in gonadotrophs and folliculo-stellate cells. Earlier in the cycle, when follistatin m R N A levels are higher, follistatin m R N A is present mainly in a subpopulation of somatotrophs and lactotrophs, although some folliculo-stellate cells, gonadotrophs, and thyrotrophs contain follistatin m R N A as well (269). The amount of follistatin m R N A in AP cell cultures depends on the time in culture, the presence of serum, and the presence of phorbol esters (311). Follistatins specifically inhibit the release and content of FSH but not that of LH or other AP hormones (498,520). Follistatin inhibits activin-stimulated FSH synthesis and secretion as well as LHRH-induced FSH synthesis and secretion (498), and it reduces the number of L H R H binding sites (498). Part of these actions of follistatin can be explained by its ability to bind activin (311,340). POSTERIOR LOBE PEPTIDES: OXYTOCIN AND VASOPRESSIN (TABLES 2, II, AND 12) Oxytocin and vasopressin, two neurohypophyseal hormones, are present in the AP as shown by immunocytochemical staining (93,2?8). Their m R N A s have been detected in rat AP (93,278,469,474), suggesting that these peptides can also be synthesised in the anterior lobe of the pituitary. Arginin-vasopressin (AVP) immunoreactivity is localized in mouse corticotropic AtT2o cells and in normal AP were it is found mainly in corticotrophs, but also in lactotrophs, gonadotrophs, and thyrotrophs, whereas it is absent in somatotrophs (278,469). Older studies report that AVP is present in less than 1% of rat AP cells and is not present in corticotrophs (279). However, its m R N A has been located in rat AP corticotrophs by in situ hybridization (469,474) and in AtT20 cells (2?8). Neurophysin, which is encoded by the same precursor, is also found in rat corticotrophs and mouse AtT2o cells (278). Thus, the corticotroph appears to be the main site of AVP production in the AP.

PEPTIDES IN ANTERIOR PITUITARY

565

TABLE 12 EFFECTS OF POSTERIOR LOBE PEPTIDES IN AP Effecton Hormone Release Pepfide

PRL

GH

Vasopressin

Oxytocin

t

ne

TSH

LH

FSH

ACTH

~

t

t

t CRF ind: ~ *--,ne

ne

f~ne

t~ne

t

Other

Other Effects Number of TSH and ACTH cells Brdu label index t POMC mRNA

Summary of data on the direct effect of peptides at AP level. See Table 3 legend for explanation of symbols and abbreviations.

The AP AVP content increases after adrenalectomy and this can be prevented by dexamethasone treatment [references cited in (278)]. Rat and mouse AP cells in culture secrete AVP into the culture medium (278,279), but, unexpectedly, this release is not stimulated by CRF (278). The AP expresses oxytocin and vasopressin receptors (68,112,204), but in AtT2o cell lines only unfunctional receptors binding oxytocin and vasopressin were reported (282). As far as the localization of those receptors is concerned, vasopressin receptors have been found on rat and sheep corticotrophs (112). Evans and Catt suggest that an AVP preferential receptor is present on corticotrophs whereas gonadotrophs carry a more oxytocin-selective receptor (116). Childs et al. demonstrated that the AVP target cells in the AP are corticotrophs and thyrotrophs and a cell that stores ACTH and TSH (81). The AP vasopressin receptors are a new type called V~b (112,204), which would explain why no AVP binding sites could be detected in autoradiographic studies using selective V~a and V2 ligands (376) and why only very few AP cells contained Via mRNA (362). As far as its in vitro effects at the AP level are concerned, AVP has an established function as ACTH-releasing peptide (357,423), directly acting on the corticotrophs, and synergic or potentiating (316,357,358,423) or additive towards CRF (63,423). However, AVP does not act synergistically with CRF to stimulate POMC gene expression (272). It possibly affects mRNA stability and/or processing and possibly has transient effects on POMC transcription (272). Oxytocin is less potent than vasopressin in stimulating ACTH release (I 16). The interaction between CRF and vasopressin on AP corticotrophs can be explained by a paracrine interaction between subpopulations ofcorticotrophs, although other explanations cannot be excluded (80,423,424). Glucocorticoids inhibit the effect of vasopressin and oxytocin on ACTH release (275,347). Both oxytocin and vasopressin stimulate LH and FSH release in vitro. In this effect oxytocin is more potent than vasopressin (116,117), which is consistent with the finding of more oxytocinselective receptors on gonadotrophs (116). Other studies found no effect of oxytocin on LH, FSH, GH, or TSH release in vitro but indicate that it can enhance PRL release (329,413). Others indicate that AVP stimulates TSH secretion (281). Apart from these effects on hormone release, AVP seems to affect cell differentiation because it enhances the number of TSHand ACTH-containing cells (81). Arginin-vasopressin increases the bromodeoxyuridine labeling index in rat AP cell cultures and interacts with CRF in this respect (306). The glycoprotein C-terminus of the AVP-neurophysin propeptide was found to have PRL-releasing activities in vitro (339), although this was denied by others (195).

HYPOTHALAMIC RELEASING FACTORS(TABLE 11) Several hypothalamic releasing and inhibiting factors are present in the AP. In this case, the demonstration of local synthesis is extremely valuable in evaluating the importance of these findings because these peptides are released by the hypothalamus into the portal blood and can be internalized by their AP target cells. All these hypothalamic factors have receptors in the AP, and direct effects on AP hormone release, hormone production, and cell differentiation are possible. However, the function of eventually locally produced releasing and inhibiting factors in the AP has not been demonstrated by experimental data. In this section we will limit data on the presence of the releasing factors in the AP without discussing their effects in the AP. Data on that issue can be found in other reviews.

Somatostatin Somatostatin immunoreactivity has been localized in AP thyrotrophs, lactotrophs, and somatotrophs but not in corticotrophs and gonadotrophs. However, this may be due to receptormediated internalization of somatostatin because the hormone release of these three cell types is affected by somatostatin (328). The presence of somatostatin-containing fibers in the AP near somatotrophs and thyrotrophs has also been demonstrated (515). Human AP GH-secreting and mixed GH/PRL-secreting adenomas release, during in vitro perifusion, higher amounts of somatostatin than their initial content [(367), and references cited therein]. This provides indirect evidence for endogenous somatostatin synthesis by the AP. It has also been shown that TRH affects the release of somatostatin by AP cells [(216,367), and references cited therein]. Recently, additional evidence for somatostatin synthesis in AP cells was found because variable amounts of preprosomatostatin mRNA were detected in normal and tumoral human AP extracts (36?) and in cultured rat AP cells by Northern blot analysis (24). In human pituitary adenomas this mRNA was found mainly in somatotropic adenomas (2?3).

Growth HormonoReleasing Factor Recently, GRF-IR was detected in normal rat AP, in the AP of rats treated with colchicine, and in AP cell cultures after 7 days in culture (61). The GRF-IR could be localized in monkey somatotrophs and teleost folliculo-stellate cells (61,327). Using reverse transcription PCR, G R F mRNA was demonstrated in human GH-producing pituitary adenomas (494), but data on normal AP are lacking. Normal pituitaries and GH-secreting human adenomas release significant amounts of GRF in an in vitro perifusion system

566

HOUBEN AND DENEF

(216). Although GRF is present in the medium only at the start of the perifusion and disappears rapidly, somatostatin stimulates GRF release from normal pituitary tissues (216).

amphibians, 7B2 itself is not secreted, but a processed product of 18 kDa is (19). Thus, 7B2 may be a precursor protein (19), the function of which remains unknown.

Luteinizing Hormone-Reh, asing ttormone

Chromogranins or Secretogranins and Related Peptides

Luteinizing hormone-releasing hormone has been detected by immunocytochemistry in gonadotrophs by several groups, although it was sometimes found in lactotrophs, in corticotrophs, or in an unidentified cell type different from gonadotrophs Ireviewed in (302)]. There are indications that this LHRH is bloodborne and internalized by AP cells after receptor binding (302). The presence of LHRH in AP cells after 4, 7, and even 21 days in culture and the finding of LHRH mRNA in the rat AP by reverse transcription PCR suggest that at least a part of the AP LHRH is synthesized locally (302,366).

The chromogranins A (ChgA), B (ChgB or SgI), and C (usually called secretogranin II, SgII) are acidic secretory proteins found in neuroendocrine tissues. Chromogranin A mRNA has been demonstrated in the human, bovine, and rat AP, whereas ChgB mRNA was detected in human AP (4,196,438) and SgII mRNA in the rat AP (4,438). Recently, a protein named secretogranin III and an mRNA encoding a chromogranin-like protein have been isolated and seem to be present in rat pituitary corticotrophs (363). Chromogranins are found in gonadotrophs, but depending on the animal species and the experimental conditions, they are detected in other cell types as well. Chromogranin A protein and mRNA and ChgB mRNA are present in normal human gonadotrophs and in null cell adenomas, whereas only ChgB mRNA is present in prolactinomas (276). In rat ChgA and ChgB are located in gonadotrophs as well, but ChgB is also found in a rat AP cell type that does not contain ChgA (128). Secretogranin II has been localized in rat thyrotrophs and gonadotrophs (87,502), in lactotrophs, and in GH3 cells (4), and it is present in all cell types of bovine AP [reviewed in (4)]. In ovine AP ChgA, ChgB, and SgII are present in gonadotrophs and corticotrophs but not in lactotrophs and somatotrophs; thyrotrophs contain only ChgA and SgII [for references see (4,128,502)]. Although ChgA and ChgB are often present together, it seems that their genes can be differentially expressed, as can be seen in human prolactinomas and other examples mentioned above (276,446). In rat, ChgA-IR in the AP reaches a maximum between day 14 and day 21 and decreases seriously in adult rats (5). Ovariectomy of female rats increases pituitary SgII and ChgA peptide and mRNA levels (4). Estrogen reverses the effect on ChgA but not on SgII (4). Similarly, estrogen treatment of AP cell cultures decreases ChgA and Sgll mRNA levels and ChgA content but has no effect on SglI content (6). Dexamethasone increases ChgA protein and mRNA without affecting the ChgB protein and mRNA or SgII (128). On the contrary, adrenalectomy significantly decreases rat AP ChgA mRNA (166). Chromogranin B mRNA in the rat GH- and PRL-secreting GH3B6 cells decreases by TRH and dexamethasone treatment and increases by estradiol treatment (265). Recently, it has been shown the mouse corticotropic ART20 cell line secretes ChgA (495). Secretion increases after treatment with dexamethasone for 48 h and CRF stimulates chromogranin secretion. The rat pituitary GH- and PRL-secreting tumor cell line GH4C~ secretes ChgB and SglI in parallel with GH and PRL (177). Secretogranin II release from rat AP is enhanced by LHRH, phorbol ester, and the G-protein inactivator NaF (87). The presence of these proteins and their mRNA in the AP is relevant in this context because it has been suggested that they function as precursor molecules tbr biologically active peptides (505). Pancreastatin, originally isolated from porcine pancreas, shows homology with ChgA ( 114,196) and the peptides GAWK [ChgB(420-493)] and CCB [ChgB(597-653)], or COOH-terminal region of ChgB are homologous to parts of ChgB (30). CCB is present in unidentified cells of the human AP, and GAWK has been shown in human somatotrophs and thyrotrophs, but not in lactotrophs, corticotrophs, or gonadotrophs (30). Porcine AP contains pancreastatin (385). Little research has been done on the possible local function of these peptides in the AP. As ChgA inhibits CRF-induced 16

Thyrolropin-Releasing Hormone A TRH precursor is present in the rat AP (139,441) and TRH-IR is found in AP by several investigators (49,76,77,302,324). Thyrotropin-releasing hormone is released by normal human AP, by prolactinomas, and by GH-secreting and nonsecreting adenomas (268). Although several studies detected TRH in secretory granules in fresh AP (76,77), Bruhn et al. have not found TRH in fresh AP tissue of rats but indicate that both TRH and pro-TRH peptides are secreted by AP cell cultures at 18 days in culture and are present in extracts of 21day-old cultures (49). Part of the AP TRH can originate from receptor-mediated internalization (324), although the presence of TRH in AP after 3 weeks in culture suggests local synthesis (49,302). In vitro experiments by Childs et al. (76) indicate that there is no appreciable uptake of exogenous TRH or [3H]TRH into the pituitary beyond the binding expected for TRH on its receptors. The release of large amounts of TRH by human adenomatous pituitary cells, and the modification of this release by dopamine and somatostatin, is suggestive for local synthesis of TRH in the AP as well (268). Thyrotropin-releasing hormone immunoreactivity is localized in thyrotrophs by most investigators, but is found additionally in gonadotrophs (49,76,302), lactotrophs (76,324), or corticotrophs (302) by others. Thyroidectomy decreases AP TRH content (77). After 3 weeks in culture, TRH is found in a cell type that contains LH and ACTH but no TSH (302).

Corticotropin-Reh,asing Factor Corticotropin-releasing factor immunoreactivity is found in rat corticotrophs but not in other AP cells. The presence of this peptide in its target cells is compatible with receptor-mediated internalization (74,78,326). To our knowledge, the presence of CRF mRNA in the AP has not been demonstrated. OTHER PEPTIDES (TABLES 2, 13, AND 14)

7B2 7B2, a secretory granule-associated protein of unknown function, has been isolated from pituitaries. The protein is present in rat, mouse, and human AP gonadotrophs and was detected in thyrotrophs by others as well (454). 7B2 mRNA is present in whole human pituitaries (291) and in amphibian intermediate pituitary (292). The basal release of 7B2 by AP cells is enhanced by K + and LHRH (54,454). In mouse corticotropic AtT2o cells and rat GHand PRL-secreting GH3 cells the secretion of 7B2 is stimulated by CRF and VIP and by TRH and VIP, respectively (381). In

PEPTIDES IN A N T E R I O R P I T U I T A R Y

567

TABLE 13 PRESENCE OF OTHER PEPTIDES IN AP

Peptide

IL-6 IL-I IL-2

7B2 Chromogranin A

Evidence for Presence or Synthesis

IR mRNA IR mRNA mRNA (AtTz0, human adenomas)

FS (mouse) C, S (human adenoma)

Peptide isolation mRNA (P) IR mRNA

G T G G, C, T (ovine) Null cell adenoma G G + cell without chromogranin A (rat) G, C (ovine) Null cell adenoma Prolactinoma G, T, L (rat) All cell types (bovine) G, C, T (ovine) GH3 C

Chromogranin B

mRNA

Secretogranin 11

mRNA

Secretogranin III Calcitonin

IR IR Labeled amino acid incorporation IR mRNA IR Labeled amino acid incorporation IR (teleosts) IR IR

CGRP DSIP

FMRF Kinins Lipocortin

Cell Type Containing Peptide

Release of Peptide by AP Cells

+

T

Receptors for Peptide in AP

+ G (human) +

ART20, C adenomas

+ ~ LHRH, K +, CRF, VIP, TRH + (AtT20) ~' Dex, CRF GH4C~

+ ~ LHRH, NaF, phorbol ester GH4CI

+

G, some S, T Fibers C (human, cat. porcine) T (mouse)

AtT20 + L, S, C GH3

+

+ ~ AVP, CRF

C, FS

Summary of data on the presence of peptides in the AP. See Table l legend for explanation of symbols and abbreviations.

K POMC peptide release and anti-chromogranin serum increases basal and CRF-stimulated 16 K peptide release, ChgA, released by mouse corticotropic AtT20 cells, may function as an autocrine inhibitor of POMC-derived peptide secretion. Chromogranin A also inhibits CRF-induced secretion in normal AP cells (495).

rat AP cells. This suggests an inhibitory action of endogenous AP calcitonin on PRL release (432). Salmon calcitonin has no effect on GH, TSH, FSH, or LH release from perifused AP cells nor on T R H - i n d u c e d TSH release, GRF-induced G H release, or PRL release induced by VIP, forskolin, phorbol myristate, or A23187 ionophore (435).

Calcitonin Calcitonin is a peptide hormone produced in the thyroid C cells and is involved in the Ca 2+ and phosphate metabolism. Calcitonin immunoreactivity is present in AP cells (100,504) and is released by 0.1% of the rat AP cells (99), but its m R N A could not be detected using c D N A to thyroid calcitonin m R N A (199,432). [3sS]Cysteine incorporation in a calcitonin-like peptide in the AP suggests the existence of a pituitary-derived calcitoninlike peptide that is synthesised in rat AP (432). Calcitonin binding sites are present in the AP (154,301) and a direct inhibitory effect of salmon calcitonin on basal (433) and TRH-induced (218) PRL release and on AP PRL m R N A levels is found in rat AP cell cultures (434). Anti-salmon calcitonin and anti-human calcitonin serum stimulate PRL release from

Calcitonin Gene-Related Peptide Calcitonin gene-related peptide (CGRP) is a peptide originating from alternative processing of the m R N A transcribed from the calcitonin gene. Genes encoding separate a- and [3C G R P were found later. Calcitonin gene-related peptide immunoreactivity could be extracted from rat and h u m a n AP and was detected in nerve fibers in rat and human AP by i m m u nocytochemistry, where it was colocalized with SP (156). Calcitonin gene-related peptide and c~- and ~ - C G R P m R N A are found in rat gonadotrophs, where C G R P - I R is colocalized with 7B2-IR, suggesting that the gonadotrophs produce C G R P (156,378); C G R P - I R is also found in some somatotrophs and thyrotrophs (156).

568

HOUBEN AND DENEF

TABLE 14 EFFECTS OF OTHER PEPTIDES IN AP Effect on Hormone Release Peptide

PRL

IL-6

$ *-~ ne

IL- 1

~ TRH ind: ~ VIP ind: +

GH

TSH

t ~ ne I'

LH

FSH

ACTH

]' ~ ne

'~ ~-, ne

$ ~ ne CRF ind: ~ ~' CRF ind: VIP ind: ~'

t

~

Other

IL-6 ~'

+ TRH ind: Anti-Calc:

ne

ne

DSIP Kinins

ACTH synthesis in AtT2o T incorporation in GH3 t POMC expression ~'

T incorporation in GH3

IL-2 7B2 Chromogranin A Calcitonin

Other Effects

nc

ne

~ ~

CRF-induced release Anti-ChgA: 16 K release PRL mRNA

?

Lipocortin- 1

~, CRF ind: t

3-Endorphin I'

Phosphoinositide metabolism '~

CRF ind:

Summary of data on the direct effect of peptides at AP level. See Table 3 legend for explanation of symbols and abbreviations.

Calcitonin gene-related peptide immunoreactivity is affected by the stage of development (156) and by gonadal steroids; e.g., it increases after treatment with high doses of estrogen (378). It decreases after ovariectomy or castration (378), and there is a sexual dimorphism in the a m o u n t of a- and 3 - C G R P - I R in the AP (149). Thyroidectomy decreases c~- and 3 - C G R P - I R in the AP (149). Binding sites for C G R P are present in the AP, and C G R P affects G H and PRL release in vivo [for references see (156)].

Delta Sleep-Inducing Peptide Delta sleep-inducing peptide (DS1P) immunoreactivity was recently shown in human, cat, and porcine AP corticotrophs and in mouse thyrotrophs (38,40,71). Mouse AP cell cultures synthesize and release a DS|P-like glycopeptide as assayed by [3H]-labeled amino acid incorporation (39). To date, however, no other p r o o f o f a local synthesis of DSIP in the AP is available. The basal release of DSIP by mouse AP cells is inhibited by AVP and CRF, but the effects of these two inhibitors are not additive. Because DSIP inhibits basal and CRF-induced A C T H release from rat AP cells, a paracrine or autocrine role of DSIP in regulating the A C T H secretion can be suggested (38). Recently, DSIP was shown to slightly enhance the LH release from AP cells obtained on the day of proestrus (86).

FMRF FMRF-amide-IR, a molluscan cardioexitatory peptide, is present in the AP of teleosts (45) but not in the AP of rats (288). FMRF-like-IR is found in the rat neurohypophysis (288).

Kinins Kinins are produced, mainly in the blood but also in other tissues, by the enzyme tissue kallikrein from precursor peptides called kininogens (212,214). They are vasodilatators. As shown

by HPLC and radioimmunoassay, three kinins, bradykinin, kallidin, and Met-Lys-bradykinin, are present in the rat AP as well as tissue kallikrein (212). Gonadectomy changes the proportions of the different kinins in the AP, and ovariectomy enhances AP kinins but orchidectomy has no effect [(212), and references cited therein]. Tissue kallikrein has been localized in rat lactotrophs, but not in somatotrophs, gonadotrophs, or corticotrophs (241), whereas kininogens have not yet been demonstrated in the AP (212). Bradykinin and kallidin stimulate phosphoinositide metabolism and PRL release in rat AP cells, but the receptor responsible for these effects is probably different from the known bradykinin (BI and B2) receptors (212). Others suggest the presence of B2 receptors on a human embryonic pituitary cell line (437). The effect of bradykinin on G H release is controversial (212,214). Stimulation of AP A C T H and 3-endorphin release by bradykinin has been reported (214).

Lipocortin- 1 Lipocortin-1 or annexin-I is a Ca 2~ and phospholipid binding protein, discovered as a Ca2+-dependent substrate for the EGF receptor tyrosine kinase. Lipocortin-1 immunoreactivity is present in human AP (206). Its distribution partly overlaps with some corticotrophs and processes of some folliculo-stellate cells (206). However, lipocortin m R N A is not detectable in the mouse corticotropic AtT2o cell line (517). Taylor et al. (468) report in an abstract that lipocortin-I inhibits CRF-, forskolin- and Bay K8644-induced A C T H release. Because dexamethasone promotes the externalization of lipocortin-1 by AP cells, lipocortin may be involved in the inhibitory effects of dexamethasone on A C T H release (468). CONCLUSION This review of the data on the presence of bioactive peptides in the AP shows the contrast between the mass of studies describing the presence of these peptides and the scarcity of

P E P T I D E S IN A N T E R I O R P I T U I T A R Y

569

studies u n i v o c a l l y d e m o n s t r a t i n g t h e i r role. M o s t a u t h o r s suggest a role in i n t e r c e l l u l a r c o m m u n i c a t i o n b u t only in the case o f VIP, g a l a n i n , n e u r o m e d i n B , / 3 - e n d o r p h i n , a c t i v i n B, a n d c a l c i t o n i n ; n e u t r a l i z i n g a n t i s e r a or a n t a g o n i s t s h a v e b e e n tested to s u p p o r t such proposals. A n o t h e r c o n t r a s t is the mass o f data o n localization of peptides in a p a r t i c u l a r cell type by means of immunocytochemistry and the paucity of data s h o w i n g the site of synthesis u n e v o c a l l y by in situ h y b r i d i z a t i o n o f peptide m R N A c o m b i n e d with i m m u n o s t a i n i n g o f t h e A P h o r m o n e costored in t h a t cell type. A r e m a r k a b l e obs e r v a t i o n is t h a t very few peptides can be localized in o n e specific cell type a n d t h a t the p r e s e n c e o f a p a r t i c u l a r p e p t i d e in a p a r t i c u l a r cell type s o m e t i m e s d e p e n d s o n h o r m o n a l c o n d i t i o n s , age, sex, a n d a n i m a l species. T h e s e findings m a y i n d i c a t e a n i m p o r t a n t f u n c t i o n a l plasticity in the local a c t i o n of these peptides.

Although a role in h o r m o n e gene expression, synthesis, a n d secretion, o n cellular differentiation, cell motility, a n d microcirculation has been proposed for A P peptides, most searches deal with the effects on h o r m o n e release. A frequent finding is that the action of most peptides on h o r m o n e release depends on experimental factors such as the in vitro test system, the type of cell culture, the species, age a n d sex of the a n i m a l used, a n d h o r m o n a l conditions. It is therefore hard to predict the effect of endogenous peptides from observations with exogenously added peptides. A few studies have shown the presence of peptide receptor subtypes in A P different from those found in other tissues. Perhaps these data indicate that separate receptors exist for the recognition of paracrine or autocrine peptide signals. This would allow distinguishing the latter signals from those derived from the same peptides reaching the A P via the portal blood.

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