Interdependence of the endocrine and immune systems

Pergamon

A&,ances in Neuroimmunology Vol. 6, pp. 297-307, 1996 © 1997 Elsevier Science Ltd. All rights reserved Printed in Great Britain 0960-5428/96 832.00

PII: S0960-5428(97)00030-7

Interdependence of the endocrine and immune systems Mireille Dardenne*~f a n d Wilson SavinoJ; *CNRS URA 1461, Universit6 Paris V. H6pital Necker, 161 rue de S~vres, 75015 Paris, France +Laboratory on Thymus Research, Department of Immunology, Institute Oswaldo Cruz. Foundation Oswaldo Cruz, Rio de Janeiro, Brazil Keywords--Neuroimmunomodulation, hormones, cytokines, hypothalamus, anterior pituitary, thyroid, thymus, thymic epithelium.

Summary The cross-talk involving the endocrine and immune systems is now largely established. These systems actually use similar ligands and receptors to establish a physiological intra- and intersystem communication circuitry, which apparently plays a relevant role in homeostasis (reviewed in Blalock, 1992). Accordingly, classical hormones such as prolactin (PRL), growth hormone (GH) and even glucocorticoids (GC) can be produced by cells of the immune system, whereas a variety of cytokines, originally described as being produced by cells of the immune system, are synthesized and released by a variety of endocrine glands and nervous tissue. Moreover, specific receptors for such distinct molecular families can be detected in both the immune and endocrine systems. © 1997 Elsevier Science Ltd. All rights reserved.

Neuroendocrine control of the immune system: the thymus paradigm Neuroendocrine control of immune function occurs at distinct levels of the immune system,

tCorresponding author.

including primary and secondary lymphoid organs, as well as sites of effector immunological activities. One of the lymphoid organs that has been widely studied in this regard is the thymus gland. Within this compartment of the immune system, bone marrow-derived T cell precursors undergo a complex process of maturation that includes selection of the T cell repertoire, with positively selected cells eventually migrating to the T-dependent areas of peripheral lymphoid organs, where they will further expand (reviewed in van Ewijk, 1991; Owen and Moore, 1995). Importantly, key events of intrathymic T cell differentiation are driven by the influence of the thymic microenvironment, a tridimensional network composed of various cell types including epithelial cells, dendritic cells and macrophages, as well as extracellular matrix elements (reviewed in Boyd et al., 1993; Savino et al., 1993). The thymic microenvironment controls thymocyte migration and differentiation through (1) secretion of a variety of polypeptides including thymic hormones and cytokines (reviewed in Bach, 1983; Haynes et al., 1990); and (2) cellcell contacts, such as the interactions occurring through classical adhesion molecules (reviewed

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in Patel and Haynes, 1993), and those involving peptide-complexed major histocompatibility complex (MHC) class I and class II proteins expressed by thymic microenvironmental cells, that interact with the T cell receptor within the context of CD8 or CD4 molecules, respectively. Lastly, microenvironmental cells bind to and interact with maturing thymocytes via extracellular matrix (ECM) ligands and receptors (reviewed in Savino et al., 1993). As detailed below, several of these interactions are targets for hormonal control. One biological activity of thymic epithelial cells (TECs4) which is under neuroendocrine control is the secretion of thymic hormones. Data from different laboratories have definitely demonstrated that secretion of thymulin, a zinccontaining nonapeptide strictly produced by TECs (Dardenne et al., 1981; Savino et al., 1982) is modulated by hormones and neuropeptides. Circulating levels of steroid, thyroid and pituitary hormones positively correlate with thymulin serum levels. Additionally, when these hormones are added in vitro, thymulin secretion is enhanced in TEC culture supernatants. For example, we and others showed that thyroid hormones (both triiodothyronine (T3) and thyroxine (T4)), upregulate thymulin secretion, both in vivo and in vitro (Savino et al., 1984; Fabris et al., 1986; Villa-Verde etal., 1993). Such an enhancing effect can be obtained even in aging individuals, and appears to depend on de novo synthesis of thymulin since, at least in vitro, it can be prevented by cycloheximide treatment (Fabris et al., 1989). Interestingly, it has been shown in humans that hypothyroidism is accompanied by low serum thymulin levels, the opposite being observed in hyperthyroidism. In both cases, appropriate treatment for the thyroid dysfunction also restores thymulin secretion to normal values (Fabris et al., 1986). In the same way, patients with prolactinomas or acromegaly exhibit high circulating thymulin levels which decrease to values comparable to normal age-matched individuals (Timsit et al., 1990, 1992). Conversely, deficiency in GH production in children is accompanied by low thymulin levels, whereas GH treatment

consistently restores this thymic endocrine function (Mocchegiani et al., 1991). In keeping with these observations, both PRL and GH enhance thymulin levels when injected into mice, as well as after being added to murine and human TEC cultures (Dardenne et al., 1989; Timsit et al., 1992). It is noteworthy that T3, PRL and GH can also enhance thymulin production in old animals (Fabris and Mocchegiani, 1985; Dardenne et al., 1989; Goff et al., 1987; Goya et al., 1992) that normally present low levels of the circulating hormone. Given the interdependence of the endocrine and immune systems, it is noteworthy that thymic hormones also modulate the production of classic peptidic hormones and neuropeptides. Initial experiments revealed that neonatal thymectomy decreases the numbers of secretory granules in acidophilic cells of the adenopituitary glands. Similarly, athymic nude mice exhibit significantly lower levels of various pituitary hormones, including PRL and GH, as well as the gonadotropins LH and FSH, and impaired hypothalamuspituitary-adrenal (HPA) axis function (Rebar et al., 1981; Daneva et al., 1995). With respect to thymic peptides, it was shown that thymosin-g4, when perfused intraventricularly, was able to stimulate LH from pituitaries and LH releasing hormone (LHRH) from the hypothalamus (Rebar et al., 1981). Additionally, another thymosin component, the MB-35 peptide, stimulates PRL and GH production (Badamchian et al., 1991). Moreover, thymopentin (a synthetic, biologically active peptide of thymopoietin, a further chemically defined thymic hormone) enhances in vitro the production of pro-opiomelanocortin derivatives such as ACTH, 13-endorphin and 13-1ipotropin (Malaise et al., 1987). Interestingly, thymosin-c~l apparently downregulates TSH, ACTH and PRL secretion in vivo, with no effects on GH levels (Milenkovic and McCann, 1992). Finally, thymulin can exhibit an in vitro stimulatory effect upon perfused rat pituitaries, enhancing GH and PRL production and, to a lesser extent, TSH and LH release (Goya et al., 1994). Altogether, these findings point to a complex bidirectional circuitry by which thymic peptides

Endocrine-immune interactions influence the hypothalamus-pituitary (HP) axis, as schematically depicted in Fig. 1. An important concept regarding the neuroendocrine control of TEC physiology is the pleiotropic nature of the effects. For example, GC and PRL upregulate the expression of high molecular weight cytokeratins by medullary TEC (Dardenne and Savino, 1990). Furthermore, extracellular matrix ligands and receptors are enhanced by thyroid and pituitary hormones (Villa-Verde et al., 1993; S avino et al., 1995). Epithelial growth is also increased in vitro following PRL and GH treatment (Dardenne and Savino, 1994a; Timsit et al., 1992). One further relevant aspect of intrathymic T cell differentiation concerns direct cell-cell interactions between thymocytes and thymic

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m i c r o e n v i r o n m e n t a l cells. We recently demonstrated that adhesion of thymocytes to cultured TECs could be enhanced by T3. Additionally, we observed that this thyroid hormone enhances t h y m o c y t e release by cultured thymic nurse cells (TNC) (Villa-Verde et al., 1993), a lymphoepithelial complex that partially supports thymocyte differentiation (see review, Villa-Verde et al., 1995). Interestingly, using the same in vitro experimental models, similar effects can be observed if TEC or TNC cultures are subjected to PRL or GH (MelloCoelho et al., 1996). More recently, we noted that rosette formation between thymocytes and thymic dendritic cells is also enhanced following treatment of dendritic cells with T3 (our own unpublished data).

Fig. 1. Influence of thymic peptides on the secretion of various hormones by cells of the HP axis. Most of the thymic peptides exhibit a stimulatory effect upon the HP axis. Thymosin o~1 appears to be inhibitory for TSH, ACTH and PRL production.

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Since hormones affect functions of microenvironmental cells related to thymocyte differentiation, it is apparent that the latter process is also under neuroendocrine control. However, besides the indirect influences mediated by the thymic microenvironment, direct effects have also been reported. Triiodothyronine upregulates intracellular calcium concentration in thymocytes (Segal and Ingkar, 1989) apparently without interfering in the cell cycle.Conversely, synthetic thyrotropin releasing hormone (TRH) enhances bromodeoxyuridine uptake by thymic cell suspensions, an effect apparently shared by PRL, and occurring by the enhancement of IL-2 production and IL-2 receptor expression (Pwalikowski et al., 1992; Mukherjee et al., 1990). In addition, GH injections in aging mice increase total thymocyte numbers and the percentage of CD3-bearing cells (Knyszynski et al., 1992), as well as the concanavalin-A mitogenic response and IL-6 production by thymocytes (Goya et al., 1992).

In keeping with the above described effects of hormones and neuropeptides upon thymus physiology, is the demonstration of receptors for such molecules in thymic cells. Using distinct methodological approaches, several groups have demonstrated, in TECs and/or thymocytes, the expression of specific receptors for a large series of hormones (see Table 1) including GC, sexual steroids, thyroid hormones, PRL, GH and others (reviewed in Dardenne and Savino, 1994b). A further and relevant aspect of the hormonal control of thymus physiology regards the possibility of various molecules, classically defined as hormones and neuropeptides, to be produced intrathymically. As depicted in Table 1, various hormones, such as PRL, GH, oxytocin, vasopressin and vasoactive intestinal peptide, whose receptors are also expressed by thymic cells, can be secreted within the organ, thus raising the hypothesis of the existence of paracrine circuits that may also be involved in intrathymic heterotypic interactions.

Table 1. Intrathymic production of pituitary hormones and neuropeptides, and expression of respective receptors a

Receptor expression Hormones GH PRL ACTH FSH LH TSH CRH OT AVP LHRH B-END VIP Somatostatin

Hormone production

Thymocyte

TEC

Thymocyte

+ + + ND ND ND ND + +

+ + ND ND ND ND ND -

+ -~ ND

+

+ + +

-

+ ND +

-

+ ND + ND + +

TEC + _ + + + + ND + + ND + +

"Expression determined by distinct techniques including ligand binding, immunocytochemistry, peptide sequencing, Northern blotting and/or polymerase chain reaction. +, positive; -, negative: ND, not determined. GH, growth hormone; PRL, prolactin; ACTH, adrenocorticotropin; FSH, follicle-stimulating hormone; LH, luteinizing hormone; TSH, thyroid-stimulating hormone; CRH, corticotropin-releasing hormone; OT, oxytocin; AVP; arginine-vasopressin; LHRH, gonadrotopin-releasing hormone; B-END, B-endorphin; VIP, vasoactive intestinal peptide.

Endocrine-immune interactions Cytokines as modulators of endocrine circuits: lessons from the h y p o t h a l a m u s pituitary axis

The immunoneuroendocrine cross-talk can also be exemplified in the HP axis (reviewed in Spangelo et al., 1995; Arzt and Stalla, 1996). It is now clearly demonstrated that IL-1 can be produced by hypothalamic neurons as well as endocrine cells from the pituitary gland (Lechan et aL, 1990; Koenig et al., 1990). Supporting an IL-1 mediated paracrine/autocrine loop in these regions, an IL- 1 receptor and its natural antagonist (IL- 1Ra) have also been detected in both hypothalamus and pituitary (Cunningham et al., 1992; Sauer et al., 1994). From a functional viewpoint, IL- 1 clearly stimulates the HPA axis (reviewed in Besedovsky and Del Rey, 1992).Additionally, an enhancing effect of this cytokine has been observed with regard to the production of GH, g-endorphin and TSH, whereas PRL secretion appears to be inhibited by IL- 1 (reviewed in Arzt and Stalla, 1996). Interestingly, the production of another cytokine by pituitary cells, namely IL-6, is augmented as a consequence of an IL- 1 stimulus (Spangelo et al., 1991). The production of IL-6 in the HP axis is actually well documented at both protein and mRNA levels, and IL-6 receptors have been demonstrated in this region (reviewed in Spangelo et al., 1995; Arzt and Stalla, 1996). The production of various adrenopituitary hormones, including PRL, GH andACTH, is enhanced by IL-6 (Spangelo et al., 1989; Lyson et al., 1991) and at least regarding ACTH, its production is secondary to an IL-6 induced increase in CRH by hypothalamic cells (Naitoh et al., 1988). It is interesting that an endocrine feedback control system appears to exist since the production of IL-6 by pituitary cells is inhibited by glucocorticoid hormones (Carmelier et al., 1991). The production of IL-2 and expression of corresponding receptors have also been demonstrated in human and murine pituitary cells (Arzt et al., 1992). Messenger RNA for this cytokine is rapidly induced by CRH, and IL-2 itself enhances proopiomelanocortin gene expression with

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consequent production of ACTH and 13-endorphin by corticotroph cells (Brown et al., 1987; Karanth et al., 1991). Additionally, IL-2 enhances PRL secretion by cultured pituitary cells, whereas both FSH and LH are inhibited (Karanth et al., 1992). Two other cytokines, TNF-~ and LIF (leukemia-inhibiting factor), can be produced by cells in the HP axis. TNF-~ stimulates GH, ACTH and TSH (but not PRL) secretion by pituitary cells, whereas LIF enhances ACTH production (reviewed in Arzt and Stalla, 1996). Conjointly, the data discussed above clearly point to an intra-HP paracrine/autocrine circuitry mediated by various cytokines (Fig. 2). Although studies in this field are relatively recent, with few cytokines being evaluated so far, we anticipate that in the next few years the expression and function of other cytokines within the HP axis will be reported. Endocrine tissues as targets for lymphocytes in autoimmunity

In addition to the physiological immunoneuroendocrine cross-talk, it is noteworthy that endocrine tissues can be targets in some autoimmune diseases; one example is the diabetes which develops in the non-obese diabetic (NOD) mouse, presently accepted as an important model for human type I diabetes. This animal develops an autoimmune diabetes with specific destruction of B cells from the endocrine pancreas, and one can induce diabetes by passive transfer of diabetogenic T cells to naive newborn animals or adult irradiated recipients (reviewed in Tochino, 1987). Although genetically determined, the onset of diabetes in NOD mice is influenced by environmental conditions (Ader etal., 1991). For example, sanitary conditions in a given colony can modify the rate of diabetes appearance. Additionally, diabetes is modulated by hormonal and stress stimuli. It is well known that in NOD mouse colonies, the frequency of diabetes in females is much higher than in males. This observation is indeed sex-hormone related since castration in males accelerates the onset of the disease and oophorectomy promotes a reversal

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:::::::~

Fig. 2. Paracrine/autocrine circuitry mediated by cytokines produced by cells of the HP axis. As detailed in the text, this notion is supported by data showing (a) production of the various cytokines by distinct cell types of the HP axis; (b) expression of receptors specific for the corresponding cytokines; and (c) biological effects of cytokines in terms of hormone secretion by distinct cells of the HP axis.

effect in females (Fitzpatrick et al., 1991). Additionally, well characterized stress conditions are able to modulate the appearance of diabetes (Lehman et al., 1991; Durant et al., 1993). The obese chicken is another example of autoimmune injury in endocrine tissue. These animals spontaneously develop a T cell dependent autoimmune thyroiditis, and correspond to an experimental model for the human Hashimoto's thyroiditis. Interestingly, a defect in GC-mediated pathways was suggested since thymocytes from obese chicken do not undergo apoptosis after in vivo GC hormone treatment. Moreover, a decreased GC response was observed following stimuli such as IL- 1 or TNF-ct (reviewed in Wick et al., 1993). Immunoneuroendocrine interactions in infectious diseases

As discussed above in relation to the thymus, an interesting aspect, originally reported to occur in

some viral diseases, is related to the production of hormones by the immune system (reviewed in Blalock, 1994). More recently it was demonstrated that HIV infection elicits lymphocytes to produce significant amounts of ACTH, through the binding of gp 120 on the lymphocyte membranes (Stefano et al., 1993). Interestingly, the 160 kDa HIV protein elicits IL- 1 production by astrocytes (Koka et al., 1995). Taken together, these findings indicate that cell binding of HIV may cause an immunoneuroendocrine imbalance, with local (and possibly systemic) changes in hormone and cytokine profiles. Moreover, it has been shown that in vivo intracerebral infusion of gpl20 augments local 1L-I, with consequent enhancement of the HPA axis (Sundar et al., 1991). Endocrine circuits also appear to be altered in Chagas' disease (a parasitic infection caused by the protozoan Trypanosoma cruzi), since it has been established that corticosterone levels are increased during the acute phase of murine T. cruzi infection (Leite de Moraes etal., 1991). On

Endocrine-immune interactions the other hand, it is noteworthy that the course of the disease is accelerated during pregnancy (Riveira et al., 1991). Infections by metazoan agents can also promote changes in neuroendocrine circuits. In the Trichinella spiralis model for gastrointestinal infection, the amount of substance P at the site of inflammation is increased (Stanisz, 1994). Interestingly, such local substance P enhancement during infection can be reversed with antiinflammatory steroids or specific degeneration of SPergic neurons (Swain et al., 1992). Substance P, somatostatin and VIP were also

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evaluated in a different model of worm infection, namely murine schistosomiasis. Interestingly, high amounts of substance P, VIP and somatostatin can be detected within mouse liver granulomas. The first two neurokines are produced by eosinophils, whereas somatostatin is a macrophage-derived product (Metwali et al., 1994). Additionally, it was shown that CD4+ T cells express somatostatin, substance P and VIP receptors (Weinstock, 1992; Cook et al., 1994; Blum etal., 1992). From a functional perspective it seems clear that substance P dramatically increases the

Fig. 3. Immune-endocrine interdependence represents one major circmtry for homeostasis (herein depicted by the Chinese ying-yang symbol of equilibrium). Disruption of such homeostatic circuitry can occur secondary to various kinds of stimuli, as shown in the surrounding spheres.

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production of IFN- ~', both in vivo and in vitro, an effect that can be specifically blocked with substance P receptor antagonists (Blum et al., 1993). In contrast, somatostatin blocks intragranuloma IFN-7 production in a dose dependent way. Accordingly, the intragranuloma IgG2a production, an IFN-7 induced event, can be up- and downregulated, respectively, by substance P and somatostatin (Blum et al., 1992). Regarding VIP functions within the schistosomatic granuloma, it was further shown that this neurokine enhances IL-5 production by T cells and decreases IL-4 release by non-T cells (Mathew et al., 1992). Conjointly, these data clearly illustrate that the intragranuloma cytokine circuitry is differentially regulated by specific neurokines. Another aspect of immunoneuroendocrine interactions in infectious diseases was illustrated from evidence showing that Schistosoma mansoni produces and secretes a variety of neuropeptides and hormones, including Met-enkephalin, ACTH, ~-MSH and g-endorphin. Most strikingly, the worm uses the host's neutroendopeptidases to make MSH, which in turn triggers a state of immunosuppression in the host. From a conceptual point of view, these data represent an example of interspecies interdependence of the endocrine and immune systems.

Conclusions and perspectives From the above discussion, the existence of physiological immunoneuroendocrine interactions that converge to homeostasis becomes apparent. In this context, one should expect endogenous as well as exogeneous changes to be able to modify such normal cross-talk (see Fig. 3). As exemplified above, in some situations endocrine glands and nervous tissue become targets of autoimmune processes. Moreover, nutritional status and toxic elements, as well as infectious agents, can yield an immunoneuroendocrine imbalance, thus disrupting homeostasis. Accordingly, one can predict that a neuroendocrine-based therapy could have benefits with respect to the onset and/or continuation of organ-specific and diffuse autoimmune diseases. However, much effort has to be

made before such procedures become clinical routines. Similarly, much work will be necessary to achieve a more precise understanding of how and at what points ~mmunoneuroendocrine interactions are disturbed in a variety of infectious diseases. However, such knowledge will hopefully be of paramount importance in designing neuroendocrine-based therapeutic procedures to be applied to infected individuals.

Acknowledgements We are greatly indebted to Martine Netter for designing the figures, Doreen Broneer for reading the manuscript and Catherine Slama for preparing the manuscript.

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