Cytokines of the Placenta and Extra-placental Membranes: Roles and Regulation During Human Pregnancy and Parturition

Placenta (2002), 23, 257–273 doi:10.1053/plac.2001.0782, available online at http://www.idealibrary.com on

CURRENT TOPIC Cytokines of the Placenta and Extra-placental Membranes: Roles and Regulation During Human Pregnancy and Parturition J. M. Bowena,b,e, L. Chamleyc, J. A. Keelana,b,d and M. D. Mitchella,b a The Liggins Institute, b Division of Pharmacology and Clinical Pharmacology, and c Division of Obstetrics & Gynecology, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand Paper accepted 5 December 2001

Summary In an earlier, companion, review, we concluded that cytokines produced by the placenta and associated membranes are likely to be involved in control of the processes of implantation and placental development (Bowen et al., 2002). In this review, we discuss evidence that cytokines continue to be part of a paracrine/autocrine regulatory network in the placenta and membranes throughout the mid and late stages of gestation. Cytokines are involved in regulation of placental growth during these later stages of pregnancy and also function to protect the fetus from pathological organisms. The evidence, while not entirely consistent, suggests that production of certain cytokines within the extraplacental membranes is altered during normal term parturition, whereas in the villous placenta evidence of labour-associated changes is much more equivocal. Roles for cytokines have been postulated in many facets of parturition, including expulsion of the fetus by uterine contractions, membrane rupture, and dilation of the cervix. Imbalances and disruptions to the cytokine milieu have been implicated in a number of diseases of pregnancy involving abnormalities of both placental growth/establishment and initiation of parturition. Cytokine secretion induced by intrauterine infection is associated with increased occurence or severity of some neonatal diseases. This wealth of data supports the view that cytokines are an integral part of a functional regulatory/communication network operating within the placental-maternal unit during normal gestation.  2002 Elsevier Science Ltd Placenta (2002), 23, 257–273

INTRODUCTION The term cytokine was originally proposed to describe secreted substances mediating an immune function (Cohen et al., 1974). However, as the understanding of cytokines and their functions has expanded, this definition has become looser and more encompassing. For the purposes of this review, we have chosen to consider as cytokines the protein messengers that are released by immune cells and affect immune cell differentiation and function, in addition to other sites of synthesis and actions. d

To whom correspondence should be addressed to: Liggins Institute and Division of Pharmacology & Clinical Pharmacology, University of Auckland Faculty of Medical and Health Sciences, Private Bag 92019, Auckland, New Zealand. Tel: + +64 9 373 7599 ex 6246; Fax: + +64 9 373 7556; E-mail: [email protected] e Current address: Department of Physiology and Biophysics, University of Illinois at Chicago, 835 S Wolcott Ave, M/C 901, Chicago, IL 60612. 0143–4004/02/040257+17 $35.00/0

In the preceding companion section to this review (Bowen et al., 2002) we presented a synopsis of the literature regarding the biosynthesis and production of cytokines by the placenta and its associated membranes. Virtually all known cytokines have been localized to these tissues during normal gestation, raising questions about the role of these molecules in the processes of pregnancy. In this review we will examine the proposed roles for placental and membrane cytokines during the later stages of pregnancy and in the initiation and progression of normal parturition, as well as the influence of these cytokines on some major diseases of gestation. The focus of this review is to provide a synopsis of the published information on these topics rather than a critical analysis. Since the scope of this review precludes an exhaustive coverage of every aspect of cytokine involvement in gestation and parturition, the reader will be directed to reviews of interest on specific sub-topics throughout.  2002 Elsevier Science Ltd

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CYTOKINE ACTIONS DURING NORMAL PREGNANCY Placental growth and apoptosis Cytokines are important factors in the evolution of the mature placenta (see companion review: Bowen et al., 2002). Cytokines have also been implicated in the induction of placental apoptosis (Nelson, 1996), which occurs in both early and late pregnancy, with the incidence of apoptosis increasing in the third trimester (Smith et al., 1997; Levy and Nelson 2000). Tumor necrosis factor (TNF)-
induces trophoblast apoptosis both alone and in concert with interferon (IFN)- (Yui et al., 1994; Garcia-Lloret et al., 1996). Morrish et al. (1998) proposed that regulation and maintenance of the mature syncytium are carried out through a balance between TNF-
, IFN-, and EGF. Imbalances in this system could thus result in abnormalities in various systems within the placenta, including apoptosis, potentially leading to placental defects.

Regulation of placental hormone production Human gestational tissues produce numerous peptide and steroid hormones (Petraglia et al., 1995b). Cytokine involvement in regulation of hormone production has been examined using a number of transformed cells and other cell lines; however, we have limited this review to studies using primary tissue except for the occasional instance where cell line information illuminates an underlying mechanism. The role of CRH and related hormones in the regulation of placental hormone production has been reviewed extensively (Fadalti et al., 2000; Challis et al., 1995; Margioris, 1993). Human chorionic gonadotropin and human placental lactogen. Human chorionic gonadotrophin (hCG) and human placental lactogen (hPL) are two of the major polypeptides secreted by trophoblast/placenta and are indicative of trophoblast differentiation. Production of hCG from placenta/trophoblast is stimulated by interleukin (IL)-1 (Masuhiro et al., 1991; Yagel et al., 1989; Seki et al., 1997), TNF-
(Li et al., 1992), GM-CSF (Garcia-Lloret et al., 1994) and M-CSF (GarciaLloret et al., 1994; Saito et al., 1993b). LIF has been reported to both stimulate (Sawai et al., 1995) and inhibit (Bischof et al., 1995; Nachtigall et al., 1996) trophoblast hCG production, while other cytokines that signal via gp130 subunit, IL-6 (Nishino et al., 1990) and oncostatin M (Ogata et al., 2000), both exert stimulatory effects. In contrast, TGF-1 inhibits trophoblast hCG production (Feinberg et al., 1994; Morrish et al., 1991; Song et al., 1996). The stimulatory actions of IL-1 and TNF-
on hCG production appear to be indirect, mediated through increases in IL-6 and activation of the IL-6 receptor system (Masuhiro et al., 1991; Li et al., 1992). Blockade of the IL-6 receptor, however, does not affect GnRH-stimulated hCG production, and GnRH does not increase trophoblast IL-6 production (Nishino et al., 1990), indicating that there are at least two receptor pathways that

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lead to increased production of hCG. Matsuzaki et al. (1992) supported this theory with the finding that TGF-1 could counteract TNF-
-stimulated IL-6 and hCG production, but not hCG production stimulated by GnRH. IL-1 also induces differentiation of trophoblast cells, possibly by stimulating release of IL-6 (Nilkaeo et al., 2000), contributing to stimulation of placental hCG production by these cytokines (Librach et al., 1994). In addition to their effects on hCG production, GM-CSF and M-CSF stimulate production of hPL by trophoblast (Garcia-Lloret et al., 1994; Saito et al., 1993b). TGF-1, in contrast, inhibits secretion of hPL (Morrish et al., 1991). Differentiation of the trophoblast into a synctium in vitro is accompanied by an increase in hCG and hPL production (Kliman et al., 1986; Hoshina et al., 1984) and at least part of the effects of M-CSF, GM-CSF and TGF-1 on production of these hormones may be carried out indirectly, through antagonistic effects on syncytial development (Saito et al., 1993b; Garcia-Lloret et al., 1994; Morrish et al., 1998; Cronier et al., 1995). The interaction between macrophages and placental hormone production has been studied by two groups. Cervar et al. (1999) used cultures of term trophoblasts and found that removal of macrophages increased hCG and hPL production. In contrast, Khan et al. (2000) found that addition of macrophage-conditioned media to purified first trimester trophoblast increased production of both hCG and hPL. These different results may reflect a change in trophoblast responsiveness to cytokines over gestation. Preterm placentae with histologic chorioamnionitis produce less hCG and hPL than do those without chorioamnionitis (Okada et al., 1997), suggesting that immune regulators released in response to infection have, overall, inhibitory effects on placental production of these hormones. CRH. IL-1 has been shown to stimulate the secretion of CRH and ACTH by human placenta (Petraglia et al., 1990). A study carried out in a transiently transfected human endometrial cell line has demonstrated that IL-1 and IL-6 increase the activity of the CRH gene promoter (Makrigiannakis et al., 1999). This effect was antagonized by the anti-inflammatory cytokine interleukin-1 receptor antagonist (IL-1RA) and treatment with indomethacin, suggesting that the effects of cytokines on CRH production were at least partially mediated by prostaglandins (Makrigiannakis et al., 1999). Steroid hormones. Consistent and conclusive evidence regarding the effects of cytokines on synthesis of progesterone by the placenta is lacking. Macrophage conditioned medium inhibits progesterone production in short term organ culture (Pederson et al., 1994), which might be a response to proinflammatory cytokines such as IL-1 and TNF-
. TNF-
reproduced this effect in the JEG-3 cell line (Pederson et al., 1995), although these results were in direct disagreement with an earlier study in which both IL-1 and TNF-
were found to stimulate JEG-3 progesterone production (Feinberg et al., 1994). Seki and coworkers also found that IL-1 stimulated progesterone

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production in a placental cell line, but observed no effect in primary placental cultures (Seki et al., 1997). Purity of cells, conditions of culture, transformation state and doses of cytokines tested are the likely contributers to these discrepant results. In contrast, estradiol production, or aromatase activity in placental cells or cell lines, has been found to be increased in response to IL-1 (Nestler, 1993), TNF-
(Pederson et al., 1995) and macrophage conditioned media (Pederson et al., 1994).

Immunological surveillance/protection against micro-organisms The production of cytokines is a significant part of the immune response in the tissues of gestation (Zdravkovic et al., 1997). Placental trophoblast, which constitute a major portion of the barrier between mother and child, are potent producers of interferons. These trophoblast-derived interferons (AboagyeMathiesen et al., 1993; Franco et al., 1999), as well as TNF-
(Paradowska et al., 1996), have been shown to impair virus replication and activity. The capacity of placental tissues to make interferons may thus help it to provide effective protection against infection of the fetus by certain viruses, such as human immunodeficiency virus (Tscherning-Casper et al., 1999; Backe et al., 1992) and herpes simplex virus (Paradowska et al., 1996). Trophoblast interferons also suppress proliferation in stimulated and resting lymphocytes, suggesting that they act to suppress the maternal immune system while protecting the fetus from infection (Zdravkovic et al., 1994). For information on the role of chemokine receptors in placental HIV infection the reader is directed to the recent review on this subject in this journal (Douglas and Thirkill, 2001). Guilbert et al. (1993) pointed out the similarities between trophoblast and macrophages including phagocytosis, invasiveness, syncytialization, and expression of specific cytokines and receptors such as the M-CSF receptor. Production of chemokines in response to M-CSF has been identified in macrophages (Orlofsky and Stanley, 1987) and murine trophoblast (Guleria and Pollard, 2000), and recruitment of immune cells to sites of placental bacterial infection in the mouse appears to be largely dependent upon placental M-CSF production and responsiveness (Guleria and Pollard, 2000).

CYTOKINES AND PARTURITION Changes in cytokine production with labour Production of mRNA or protein for many cytokines has been shown to change during normal labour and parturition. These alterations may play a significant role in the processes that culminate in successful delivery. Concentrations of inflammatory cytokines in amniotic fluid, for example, increase towards term in normal pregnancies, and may play a regulatory

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role in parturition by stimulating the local production of prostaglandins and collagenases. Interferons. Evidence for significant alterations in interferon production by gestational tissues with onset of labour is equivocal. Production of IFN- by decidual cells in vitro is significantly decreased when cells are prepared from decidua collected after labour as compared to those collected before the commencement of labour (Jones et al., 1997). However, in an immunohistochemical study, Vives et al. (1999) reported no decline in decidual IFN- protein after labour, although staining for IFN- was decreased in trophoblast following vaginal delivery. In contrast, another study found that IFN- content increased in supernatants of placental, amnion, and choriodecidual homogenates following labour (Veith and Rice, 1999). These authors did not find immunoreactive IFN- in amniotic fluid at any stage of pregnancy, although it has been detected in another study (Olah et al., 1996), in which it was reported that concentrations of IFN- did not increase with exposure to labour. There was, however, an association between the concentration of IFN- and that of IL-6, which does increase following labour (Olah et al., 1996). The most likely conclusion to be drawn from these data is that changes in interferon production do not play a key role in processes associated with labour and delivery. Inflammatory cytokines. The onset of labour at term induces elevations in amniotic fluid concentrations of IL-1 (Romero et al., 1990b; Gunn et al., 1996; Opsjon et al., 1993), IL-6 (Gunn et al., 1996) (Laham et al., 1996a; Romero et al., 1990a; Olah et al., 1996; Opsjon et al., 1993; Saito et al., 1993a; Santhanam et al., 1991), and TNF-
(Romero et al., 1992a; Opsjon et al., 1993). Concentrations of these cytokines in amniotic fluid appear to vary in an interrelated manner (Gunn et al., 1996; Halgunset et al., 1994) and to correlate with the amount of granulocyte infiltration observed in the placentae (Halgunset et al., 1994). TNF-
, IL-1
, IL-6 and IL-8 can be detected in cervicovaginal fluids before labour in the third trimester of pregnancy, particularly in women with bacterial vaginosis or who deliver preterm with associated intraamniotic infection (Inglis et al, 1994; Rizzo et al., 1996; Wennerholm et al., 1998; Mattsby-Baltzer et al., 1998). Concentrations of inflammatory cytokines in cervicovaginal secretions increase during spontaneous term labour (Cox et al., 1993; Steinborn et al., 1996), peaking at the time of complete cervical dilation. Cervicovaginal fluid levels of TNF-
increases markedly after the rupture of the fetal membranes (Steinborn et al., 1996). Exposure to labour at term results in increases in IL-1
production by the placenta (Taniguchi et al., 1991; Laham et al., 1996b), amnion (Laham et al., 1996b), choriodecidua (Laham et al., 1996b), and unseparated fetal membranes (Gunn et al., 1996). Expression of IL-1 mRNA is also increased with labour in the amnion, chorion, and isolated decidua (Dudley et al., 1996b). Release of IL-1 by placental cell cultures and explants has been reported to increase following labour (Steinborn et al., 1996; Taniguchi et al.,

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1991). However, another study did not find an increase in this cytokine in placental homogenates (Keelan et al., 1999). Conversely, Steinborn et al. (1996) did not find an increase in production of IL-1 by decidual cell cultures isolated after labour, but an increase in IL-1 concentrations in extracts of decidua has been reported (Ammala et al., 1997). Concentrations of IL-1 also increase in amnion extracts following labour (Keelan et al., 1999). Synthesis and release of IL-6 also appears to be increased by labour in gestational tissues. According to Dudley et al. (1996b) mRNA for IL-6 is rarely detected in membranes obtained before the onset of labour, but is readily located in amnion, chorion, and decidua following labour at term. IL-6 protein is also increased following labour in amnion and choriodecidual tissue extracts (Keelan et al., 1999) and cell cultures (Laham et al., 1996a) although in vitro production by amnion explants (Simpson et al., 1999) and isolated decidual cultures (Steinborn et al., 1996) is not increased. Term labour is reportedly associated with strong immunoreactive staining for both IL-1 and IL-6 in endothelial cells of the placenta (Steinborn et al., 1999). These authors earlier reported an increase in IL-6 production by the placenta following the onset of spontaneous term labour (Steinborn et al., 1996) which they attributed to placental endothelial cell production (Steinborn et al., 1998). However, other studies have reported that exposure to labour does not increase IL-6 release from placental cultures (Laham et al., 1996a; Matsuzaki et al., 1993) or IL-1 and IL-6 tissue content (Keelan et al., 1998). Messenger RNA for TNF-
is increased in amnion, chorion, and decidua with labour at term (Dudley et al., 1996b), although release from decidual cell cultures is not affected by labour (Steinborn et al., 1996). Release of TNF-
from placental cultures, in contrast, is increased following exposure to term labour (Steinborn et al., 1996), apparently originating from placental macrophages (Steinborn et al., 1998). Anti-inflammatory cytokines. A withdrawal of antiinflammatory cytokine actions during labour might be anticipated to facilitate inflammatory processes associated with parturition. While exposure to labour has been reported to decrease secretion of IL-10 from choriodecidua (Simpson et al., 1998), others have reported no change in amniotic fluid IL-10 levels (Greig et al., 1995; Jones et al., 1997; Dudley et al., 1997a) or in decidual IL-10 production (Jones et al., 1997) with labour. Amniotic fluid IL-4 concentrations are only rarely elevated following normal term labour (Dudley et al., 1996a). IL-1 receptor antagonist (IL-1RA) is present in extremely high concentrations in amniotic fluid in mid to late gestation, but there is no evidence of an increase associated with parturition (Romero et al., 1992b). Decidual IL-1RA expression is similarly unaffected by labour (Ammala et al., 1997), as are cord blood levels (Hata et al., 1996). Only maternal plasma levels of IL-1RA have been reported to be elevated with labour (Austgulen et al., 1994). TGF- and the related molecule MIC-1 are present in amniotic fluid at term

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but changes in their concentrations with parturition have not yet been determined (Lang & Searle, 1994; Heikkinen et al., 2001; Moore et al., 2000). Chemokines. IL-8 concentrations in amniotic fluid not only increase from early pregnancy to term but increase largely and consistently with the onset of spontaneous term labour (Romero et al., 1991; Laham et al., 1993; Saito et al., 1993a). Levels of IL-8 in the lower uterine segment are also elevated with labour (Osmers et al., 1995a). Some studies have indicated that labour does not increase IL-8 release from explants of choriodecidua, amnion, or placenta (Laham et al., 1999; Shimoya et al., 1992). Contradictory studies report increased IL-8 production from placental explants (Elliott et al., 1998) and increased IL-8 concentrations in tissue extracts of amnion and choriodecidual tissue (Keelan et al., 1999) following spontaneous labour. Concentrations of RANTES in amniotic fluid increase with the onset of term labour (Athayde et al., 1999). Amniotic fluid concentrations of the chemokines GRO-
and IL-16, however, do not appear to alter in response to this stimulus (Cohen et al., 1996; Athayde et al., 2000). Other cytokines. Amniotic fluid concentrations of GM-CSF increase throughout gestation, and increase additionally with labour (Bry et al., 1997), as do concentrations of G-CSF (Saito, et al., 1993a). LIF is undetectable in amniotic fluid of normal pregnancy at midtrimester and at term, but is observed in amniotic fluid following the onset of labour (Waring et al., 1994). In the placenta, increases in mRNA and protein for IL-15 have been shown to occur following the onset of labour at term (Agarwal et al., 2001). In summary, analysis of cytokine/chemokine expression, production rates and abundance in tissues and amniotic fluid support a general labour-associated increase in production of pro-inflammatory cytokines by the gestational membranes. The evidence regarding changes in placental production is much more equivocal, while production of anti-inflammatory cytokines does not appear to be greatly influenced by labour.

Regulation of myometrial contractility The uterine smooth muscle remains quiescent throughout pregnancy, allowing development of the fetus to occur in a stable environment. At the time of labour, however, intense, synchronized contractions of the myometrium occur over a short period and are responsible for expulsion of the fetus from the uterus. Initiation of myometrial contractions requires conversion of the myometrium from a quiescent to an activated tissue. Changes in local concentrations of several factors or their receptors have been implicated in this transition (reviewed by Keelan et al., 1997; Lye, 1994). Prostaglandins. Prostaglandins E2 and F2
are potent stimulators of myometrial contractility and have long been appreciated to be critical factors in the initation of labour. Hansen

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et al. (1999) have reviewed the effects of cytokines on regulation of enzymes involved in prostaglandin biosynthesis and metabolism in gestational tissues. Production of prostaglandins by cells from the amnion (Bry and Hallman, 1992; Romero et al., 1989a, b), chorion (Lundin-Schiller and Mitchell, 1991), decidua (Mitchell et al., 1990), and myometrium (Hertelendy et al., 1993; Molnar et al., 1993; Todd et al., 1996; Pollard and Mitchell, 1996a, b; Grammatopoulos and Hillhouse, 1999) is enhanced by the inflammatory cytokines IL-1 and TNF-
, probably through increased expression of prostaglandin H synthase-2 (Rauk and Chiao, 2000; Hansen et al., 1999). IL-6 has also been shown to stimulate prostaglandin production by the amnion and decidua (Mitchell et al., 1991a), while MIP-1
stimulates amnion and chorion cell prostaglandin production (Dudley et al., 1996). Prostaglandin concentrations can also be modulated through regulation of metabolic inactivation. The enzyme that catabolizes prostaglandins to inactive metabolites, 15hydroxyprostaglandin dehydrogenase (PGDH), is abundant in the chorion, placental trophoblast, and (to a lesser extent) the decidua (Germain et al., 1994; Cheung et al., 1992; Erwich and Keirse, 1992). Its activity may prevent prostaglandins in the amniotic fluid from acting upon the myometrium. PGDH expression and activity in gestational membranes and cultured chorionic trophoblast is decreased by IL-1 and TNF-
(Brown et al., 1998; Mitchell et al., 2000). PGDH protein and activity in chorionic trophoblast of the lower uterine segment has been shown to decrease with term labour, possibly contributing to the activation of the myometrium (Van Meir et al., 1997). Cytokines can also act to decrease prostaglandin production by gestational tissues. TGF-1 decreases basal and cytokinestimulated prostaglandin production from amnion and decidual cells (Berchuck et al., 1989; Bry and Lappalainen, 1994), while IL-1RA and TGF-1 both suppress IL-1-induced PG production in the myometrium (Todd et al., 1996). IL-4 decreases prostaglandin production from decidual cells while increasing production of IL-1RA (Bry and Hallman, 1992), and decreases inflammatory cytokine-stimulated prostaglandin production by placenta/trophoblast cultures, as does IL-10 (Pomini et al., 1999; Goodwin et al., 1998). However, both IL-4 and IL-10 have also been reported to stimulate the release of prostaglandins and inflammatory cytokines by some gestational tissues (Adamson et al., 1993, 1994; Simpson et al., 1999), while IL-1RA has been found to increase prostaglandin production by decidual cells (Mitchell et al., 1993a). This has led to the hypothesis that term labour is associated with a withdrawal or reversal of anti-inflammatory agents as part of an evolutionary adaptation to accelerate inflammatory processes necessary for successful labour and delivery (Simpson et al., 1998). Endothelins. Endothelins are potent activators of the myometrium (Word et al., 1990). They may also act by stimulating prostaglandin production by endothelial cells (Mitchell et al., 1990). Endothelins are produced in the placenta (Benigni et al.,

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1991), decidua and pregnant myometrium (Maggi et al., 1994). Expression of endothelin mRNA in these tissues increases towards the end of gestation (Fant et al., 1992; Maggi et al., 1994). Production of endothelins by the amnion (Sunnergren et al., 1990) is stimulated by treatment with the inflammatory cytokines IL-1, IL-6, and TNF-
(Mitchell et al., 1991; Casey et al., 1991). TGF-1 and IL-1
have also been shown to stimulate the synthesis of endothelin-1 in endometrial stroma (Casey et al., 1993).

Membrane remodelling and rupture Rupture of the fetal membranes is an essential part of normal parturition. Premature rupture of the membranes (rupture prior to onset of labour) is associated with increased risk of intrauterine infection, preterm delivery, and neonatal morbidity and mortality (see Parry and Strauss, 1998 and BryantGreenwood and Millar, 2000 for recent reviews). Cytokines may be involved in the initiation and progression of processes involved in rupture of the membranes at term and preterm, particularly when associated with intrauterine infection and chorioamnionitis. Morphological examination of the amnion suggests that the membrane does not undergo a widespread process of degeneration at term (Yoshida and Manabe, 1990). Rather, localized weakening of the membrane, with reduced cytotrophoblast and decidual thickness, may occur at a specific rupture point overlying the cervix (Malak and Bell, 1994; McLaren et al., 1999). Digestion of extracellular matrix of the fetal membranes occurs at term and is carried out largely by locally-produced matrix metalloproteinases (MMPs; reviewed by BirkedalHansen et al., 1993). MMP activity is negatively regulated by a family of inhibitory proteins (tissue inhibitors of matrix metalloproteinases; TIMPs). Changes in activity of plasminogen activator, MMPs and TIMPs in amniotic fluid and gestational tissues are associated with the onset of labour and rupture of the fetal membranes (Koay et al., 1986; BryantGreenwood and Yamamoto, 1995; Draper et al., 1995; VadilloOrtega et al., 1995, 1996; Athayde et al., 1998; Riley et al., 1999). Cytokines may be among the factors responsible for driving the increased levels of MMP expression and activity in the membranes associated with rupture. Intrauterine infection has been associated with higher MMP-9 concentrations in amniotic fluid, whether or not membrane rupture occurs (Athayde et al., 1998). This increase in MMP-9 may reflect an increase in leukocyte colonization of the amniotic fluid. TNF-
, IL-1, IL-6 and M-CSF have all been shown to increase MMP gelatinase secretion by first trimester trophoblast, while TGF- decreases this activity (Meisser et al., 1999a, 1999b). TNF-
stimulates production of MMPs (
1 and
3) and plasminogen activator by chorion and decreases the production of TIMP (So et al., 1992), while IL-1
increases synthesis of MMP-1 by cultured chorionic cells (Katsura et al., 1989). Treatment of amniochorion explants with lipopolysaccharide, a stimulator of cytokine release,

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also results in an increase in synthesis and release of MMP-2 and a decrease in the synthesis and release of its tissue inhibitor (Fortunato et al., 2000). Concentrations of IL-8, a chemoattractant for leukocytes, have been significantly correlated with those of MMP-9 in the amnion and chorion during the later stages of cervical dilation (Osmers et al., 1995a). IL-8 production in chorion and amnion is stimulated by IL-1 and TNF-
(Ito et al., 1994; Trautman et al., 1992; Keelan et al., 1997). Interestingly, both IL-8 production and collagenase activity in the fetal membranes are increased by mechanical stretching (Maehara et al., 1996; El Maradny et al., 1996). In addition to digestion of the extracellular matrix, there is some evidence that apoptosis contributes to weakening of the fetal membranes prior to rupture, particularly in the chorion layer at the site of rupture (Runic et al., 1998; McLaren et al., 1999). Expression of the proapoptotic genes bax and p53 is increased in amniochorion from pregnancies complicated by premature rupture of the membranes, while expression of the antiapoptotic gene bcl-2 is decreased (Fortunato et al., 2000). Apoptotic cell death may be a reaction to the destruction of extracellular matrix in the membranes or a significant and separate part of membrane thinning and rupture. TNF-
, in concert with IFN, induces trophoblast apoptosis (Yui et al., 1994; Garcia-Lloret et al., 1996). TNF-
and other family members may thus be involved in the normal rupture of fetal membranes at term, through induction of apoptosis. Cervical ripening Cervical ripening, remodelling and softening of the cervix, is a requirement for the normal onset and progress of labour. The processes of cervical ripening are similar to those involved in induction of membrane rupture, including changes in extracellular matrix composition, invasion of neutrophils, and tissue remodelling by proteolytic enzymes (Liggins, 1981; Uldbjerg et al., 1983; Granstrom et al., 1989; Osmers et al., 1992; Knudsen et al., 1997; Winkler and Rath, 1999). Cytokines, particularly IL-8, have been implicated in the process of cervical ripening. Briefly, IL-8 synthesis and secretion is greatly increased in term versus non-pregnant cervix and concentrations of IL-8 in the cervix and lower uterine segment increase with cervical ripening (Sennstrom et al., 1997, 2000; Winkler et al., 1998a). The increase in IL-8 during cervical ripening correlates with increases in leukocyte infiltration and concentrations of MMPs in the tissue (Osmers, et al., 1995a, b; Winkler et al., 1999a, a). Concentrations of IL-1, TNF-
and IL-6 in the lower uterine segment also increase with cervical dilation (Winkler et al., 1998a, b) and have been shown to affect production of TIMPs and MMPs by human cervical fibroblasts and smooth muscle cells (Ito et al., 1990; Sato et al., 1990; Ogawa et al., 1998; Watari et al., 1999). Increases in IL-6, G-CSF and MCP-1, cytokines which affect proliferation and activation of immune cells, also occur with cervical ripening (Sennstrom et al., 2000; Denison et al., 2000).

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While the majority of cytokine effects on cervical ripening are likely to be induced by locally produced cytokines, it is possible that cytokines secreted by the placenta and membranes may have an indirect effect. IL-1 has been shown to induce IL-8 secretion by human cervical fibroblasts in vitro, alone and in concert with TGF-1 and growth factors (Winkler et al., 1998c, 2000). PGE2, secretion of which is influenced by many cytokines, also stimulates IL-8 release from cervical tissue (Denison et al., 1999), affects proteolytic enzyme activity (Denison et al., 1999) and induces cervical ripening (Ekman et al., 1983).

CYTOKINES AND DISEASES OF GESTATION Pre-eclampsia/intrauterine growth retardation Pre-eclampsia, the defining characteristics of which are the onset of hypertension, proteinuria, and edema during pregnancy, is a major cause of maternal morbidity and mortality. Although the etiology of pre-eclampsia is complex (see reviews by Broughton et al., 1994; Taylor & Roberts, 1991; Redman et al., 1999), it is a disease in which the presence of the placenta is obligatory. It can occur in pregnancies without fetal tissue present (complete molar pregnancy) and is resolved by delivery or surgical removal of the placenta. While the mechanisms of pre-eclampsia are manifold, a defect in trophoblast invasion has been established as a consistent contributory factor. Trophoblast invasion into decidual and myometrial spiral arteries is decreased in pre-eclamptic pregnancies, and also in some pregnancies with intrauterine growth restriction (IUGR; Meekins et al., 1994; Khong et al., 1986). These trophoblast abnormalities can be mimicked in vitro by hypoxic conditions and are associated with a decrease in invasive capability (Zhou et al., 1998; Genbacev et al., 1996). This suggests that a causal factor in pre-eclampsia may be continued placental hypoxia after the first trimester. Expression of TGF-3 in the placenta is also increased by hypoxia (Caniggia et al., 2000), and alterations in expression of this cytokine have been proposed as one causal factor in the failure of trophoblastic invasion and maturation. A marked decrease in transcription of TGF-3 occurs after 9 weeks of gestation in normal pregnancy, and is correlated with an increase in trophoblast differentiation and invasion (Caniggia et al., 1999). TGF-3 is over-expressed in placentae from pre-eclamptic pregnancies; inhibition of TGF-3 expression or activity restores the invasive capability of explants of preeclamptic placentas to normal levels (Caniggia et al., 1999). TNF-
protein has also been identified in endovascular trophoblast during invasion of the spiral arteries and may be a regulatory factor in this process (Pijnenborg et al., 1998). Vascular defects of the placenta in pre-eclampsia may result in focal areas of the tissue receiving inadequate oxygen or nutrient supply, particularly in the later stages of pregnancy. Focal ischemia within the placenta may also result in the generation of diffusible factors from the hypoxic areas. These

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factors may initiate the maternal syndrome of pre-eclampsia, which is postulated to result from generalized endothelial damage and dysfunction (Roberts et al., 1989). Circulating factors that affect vascular endothelial cell function have been found to exist in pre-eclamptic women (Ashworth et al., 1998; Hayman et al., 2000) and cytokines have been proposed to constitute some of these factors. Incubation in hypoxic conditions has been shown to stimulate production of TNF-
and IL-1 by placental explants (Benyo et al., 1997). These cytokines have multiple actions on endothelial cells, including promoting coagulation and inflammatory responses (reviewed by Pober and Cotran, 1990). There is also circumstantial evidence for a role of TNF in oxidative damage during pre-eclampsia (reviewed by Stark, 1993). Increases in concentrations of serum IL-8 with pre-eclampsia has been reported, leading to increased activation of neutrophils (Claman et al., 1997). Increased superoxide production by neutrophils of pre-eclamptic women, in association with a serum activating factor, has also been reported by Tsukimori et al. (1993) although neither they nor others (Greer et al., 1994) observed an increase in serum IL-8 with pre-eclampsia. The potential role of neutrophils in the endothelial damage associated with pre-eclampsia is reviewed by Clark et al. (1998) and Vinatier and Monnier, (1995). Placental production rates of several cytokines are altered by pre-eclampsia. Increases in placental TNF-
expression and secretion (Wang and Walsh, 1996) and increases in immunodetectable IL-2 in the decidua (Hara et al., 1995) have been reported for tissues from pre-eclamptic pregnancies compared to uncomplicated gestation. Production of IL-6 (Kauma et al., 1995), IL-8 (Wang et al., 1999), IL-10 (Hennessy et al., 1999) and IL-15 (Agarwal et al., 2001) by the placenta have been reported to be decreased with pre-eclampsia, while IL-1 production is increased (Munno et al., 1999). Pre-eclampsia/ IUGR is also associated with changes in concentrations of amniotic fluid cytokines. Elevations in IL-6 and IL-8 in midtrimester amniotic fluid have been associated with the subsequent onset of pre-eclampsia (Nakabayashi et al., 1998). In patients with pre-eclampsia/IUGR, TNF-
in the amniotic fluid during labour is also elevated compared to normal pregnancies, while amniotic fluid concentrations of G-CSF, GM-CSF, and IL-1 are reduced (Stallmach et al., 1995a). Another study has reported no difference in bioactive TNF-
or IL-6 in amnotic fluid from pre-eclamptic or normal pregnancies at the time of delivery, but a decrease in bioactive IL-1 (Opsjon et al., 1995). These authors also reported that the onset of labour resulted in elevations in amniotic fluid TNF-
, IL-1, and IL-6 in pre-eclamptic pregnancy similar to those observed in normal pregnancy (Opsjon et al., 1995). The apparent contradictions between studies using immunological detection of cytokines and bioactivity studies may reflect changes in inhibitors or binding proteins for cytokines during pre-eclamptic pregnancy. IUGR dissociated from preeclampsia is also associated with altered cytokine production. IUGR is associated with increases in amniotic fluid IL-10 (Heyborne et al., 1994). In addition, decidual tissue derived

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from pregnancies complicated by idiopathic IUGR contains less mRNA for IFN- than decidual tissue from normal pregnancies, while expression of IFN- mRNA by trophoblast is increased in cases of IUGR (Vives et al., 1999). Disruption in synthesis of some prostaglandins, notably prostacyclin and thromboxane, may play a role in vascular disorders of pre-eclampsia (reviewed by Friedman, 1988). During normal pregnancy the placenta produces equivalent amounts of thromboxane and prostacyclin; however, in preeclamptic pregnancy production of thromboxane greatly exceeds that of prostacyclin (Walsh, 1985). This disruption of placental prostaglandin synthesis is not observed in IUGR without hypertension (Sorem and Siler-Khodr, 1995). A decrease in placental IL-8 production, associated with the decrease in prostacyclin, has been reported for villous tissues from pre-eclamptic pregnancies. Treatment of these tissues with IL-8 improves placental prostacyclin production (Wang et al., 1999), suggesting a role for this cytokine in maintaining prostaglandin balance during pregnancy.

Preterm delivery/Preterm premature rupture of membranes There is strong evidence that elevated cytokine production in gestational tissues is associated with spontaneous preterm labour. While the causes of spontaneous PTB are perceived to be multifactorial, ascending infection of the fetal membranes and amniotic cavity, originating from pathogenic bacteria in the vaginal tract, is a major cause of preterm birth, particularly in deliveries <32 weeks gestation (Romero et al., 1994; Gibbs et al., 1992). Intra-amniotic infection (defined as positive amniotic fluid culture) is associated with about 12 per cent births <37 weeks’ gestation with intact membranes; about one third of these (i.e. 4 per cent) have clinical chorioamnionitis (Romero et al., 1994). About one-third of all pregnancies delivered with preterm premature rupture of membranes (PPROM) are infected, and it has been proposed that preterm birth and PPROM represent different manifestations of a common etiology (Gomez et al., 1997a). The widely accepted view of the pathophysiology of infection-driven PTB is that the infective agent infiltrates the decidua and chorion, eliciting an inflammatory reaction accompanied by leukocytic infiltration of the membranes (Mitchell et al., 1991b; Gibbs et al., 1992; Gomez et al., 1997b). If unchecked, the pathogen may cross the amniotic barrier and infect the amniotic fluid and fetus. Cytokines and chemokines released by the resident cells of the membranes and activated leukocytes amplify the inflammation, associated with the release and activation of matrix metalloproteinases (MMPs) which degrade the collagen/ fibronectin matrix of the membranes, predisposing them to rupture (Polzin and Brady, 1998; Gomez et al., 1997a; Athayde et al., 1998; Winkler and Rath, 1996; Fortunato et al., 1999, 2000; Vadillo-Ortega et al., 1996). Prostaglandins and other uterotonins are also released by the inflammatory response,

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Placenta (2002), Vol. 23

Uterine Contractions

Increased uterine Prostaglandin/ response thromboxane Endothelin production production Initiating Signal: e.g. Ascending intrauterine infection or onset of labour

Increased/Altered Cytokine Production

Leukocyte Infiltration

Cervical ripening

Production of proteolytic enzymes

Birth

Apoptosis

Membrane Rupture

Figure 1. Cytokines play a central role in processes involved in the metabolism of term and preterm parturition.

resulting in cervical ripening, loss of myometrial quiescence and onset of uterine contractions (Romero et al., 1994; Mitchell and Trautman, 1993). Figure 1 provides a diagramatic overview of this concept of preterm birth. Once initiated, contractions intensify the inflammatory response in the gestational membranes through, in part, activation of stretch-responsive genes and mechanical distension of the membranes and cervix (El Maradny et al., 1996; Maehara et al., 1996; Riemer and Heymann, 1998). Several studies have documented enhanced cytokine & chemokine expression and/or production by the decidua and fetal membranes in response to bacteria or bacterial products (Laham et al., 1994, 1996a; Fortunato et al., 1996; Dudley et al., 1996d, 1997b; Keelan et al., 1997; Simpson et al., 1998). We have examined cytokine levels in tissue extracts from preterm deliveries and concluded that IL-1, IL-6 and IL-8 concentrations in the extraplacental membranes, but not placental villi, are elevated in spontaneous preterm deliveries (Keelan et al., 1999). These data support the contention that the fetal membranes and decidua contribute towards the elevated concentrations of cytokines measured in amniotic fluid from pregnancies delivered preterm (Saito et al., 1993a; Laham et al., 1994; Dudley et al., 1996c; Andrews et al., 1995; Tsuda et al., 1998). In preterm deliveries associated with chorioamnionitis or intra-amniotic infection, markedly elevated concentrations of cytokines and chemokines in amniotic fluid have been reported in numerous studies. Amniotic fluid IL-6 appears a particularly responsive indicator of intrauterine infection (Romero et al., 1993; Saito et al., 1993a; Coultrip et al., 1994; Andrews et al., 1995; Tsuda et al., 1998; Negishi et al., 1996; Hsu et al., 1998b; Arntzen et al., 1998), although elevated levels of IL-1 (Arntzen et al., 1998; Stallmach et al., 1995b), IL-4 (Dudley et al., 1996a), IL-8 (Saito et al., 1993a; Cherouny et al., 1993; Stallmach et al., 1995b; Hsu et al., 1998b), IL-16 (Athayde et al., 2000), TNF-
(Arntzen et al., 1998; Stallmach et al., 1995b; Romero

et al., 1989b), G-CSF (Saito et al., 1993a; Stallmach et al., 1995a), GRO-
(Cohen et al., 1996; Hsu et al., 1998a), MIP-1
(Dudley et al., 1996c) and RANTES (Athayde et al., 1999) have all been described in preterm deliveries with intrauterine infection. Not all cytokines measured, however, appear to be similarly responsive to upregulation in the presence of infection. IL-4 (Henriques et al., 1998) abundance in the fetal membranes and decidua appears to be similar in term or preterm deliveries, irrespective of infection status. Although IL-10 concentrations in amniotic fluid have been reported to be elevated by one group (Greig et al., 1995), no significant differences were detected by another (Dudley et al., 1997a). It is, perhaps, of significance that these cytokines have ambiguous roles in an inflammatory setting and in some circumstances can exhibit anti-inflammatory properties. The role of the villous placenta in the cytokine response to ascending infection and onset of preterm labour is more equivocal. Shimoya et al. (1992) reported elevated rates of IL-8 production by placental explants from pregnancies with chorioamnionitis vs non-infected pregnancies, and similar findings have been reported for IL-6 (Matsuzaki et al., 1993). Steinborn et al. (1996), in contrast, found enhanced placental production of IL-1, IL-6 and TNF-
in non-infected preterm deliveries, but not those with confirmed chorioamnionitis. This group also reported that preterm delivery was accompanied by increased production of IL-1 and IL-6 by placental CD-11b-positive cells (i.e. macrophages) in the stromal villi relative to similar cells from spontaneous term deliveries (Steinborn et al., 1998). However, although about 50 per cent of these pregnancies had evidence of maternal sepsis, none had intraamniotic infection, making this a rather unrepresentative group. We have reported a lack of any significant differences in concentrations of either IL-1, IL-6 or IL-8 in placental extracts from preterm vs term deliveries, irrespective of infection status (Keelan et al., 1999). Elevated maternal

Bowen et al.: Cytokines of the Placenta and Extra-placental Membranes

serum IL-6 concentrations have been reported to be diagnostic for intrauterine infection-associated preterm labour, providing indirect evidence of a placental involvement in some instances of infection-driven preterm deliveries (Greig et al., 1997), although these observations have not been confirmed in other studies (Salafia et al., 1997). Finally, a decidual, or even cervical, source of cytokines measured in the maternal circulation cannot be discounted. The major cellular source of cytokine production in the presence of intrauterine infection is likely to be the leukocytes that are recruited into the gestational membranes to fight the infiltrating pathogen. These cells, which are abundant in the majority of tissues from pregnancies with microbial invasion of the amniotic cavity, have been shown to be activated in infection-associated preterm deliveries (Matsubara et al., 1999). Furthermore, cytokine levels in choriodecidual and amniotic membranes from preterm deliveries are strongly correlated with leukocyte count as are levels of TNF-
, IL-1 and IL-6 in amniotic fluid from spontaneous preterm deliveries (Halgunset et al., 1994; Negishi et al., 1996), suggesting that these cells are a major source of the cytokines measurable in the tissues or fluids concerned. Alternatively, their presence could act as a stimulator for cytokine release by cells normally resident in the membranes. In contrast to the majority of findings, one group of researchers has reported elevated cytokine production rates in placental tissues from non-infected preterm deliveries, while infected tissues exhibit cytokine production rates that are similar to those from term (uninfected) tissues (Steinborn et al., 1996). These investigators also failed to find differences in decidual cytokine production rates from term and preterm deliveries (Steinborn et al., 1996). Interestingly, they have reported observing enhanced IL-1 and IL-6 production by placental endothelial cells from chorioamnionitis-negative pregnancies, in contrast to increased cytokine abundance in leukocyte-infiltrated amniochorion membranes from pregnancies with intraamniotic infection (Steinborn et al., 1999). A variety of studies have illustrated the mechanisms through which pro-inflammatory cytokines released by infected gestational tissues initiate preterm contractions leading to labour onset. The main effect appears to be through up-regulation of prostaglandin F2
and E2 production by amnion, chorion and decidual cells, principally via enhanced expression of PGHS-2 combined with increased cPLA2 activity (Bry et al., 1994; Edwin et al., 1996; Hansen et al., 1999; Mitchell et al., 1993b; Trautman et al., 1996). IL-1 and TNF-
, in particular, are potent inducers of PG synthesis within gestational tissues, and also appear to exert a negative effect on the main PG metabolizing enzyme, PGDH, which is localized to the chorion and (to a lesser extent) the decidua (Challis et al., 1999). A number of other cytokines, including IL-2, IL-6, and LIF, have also been reported to stimulate PG biosynthesis in the gestational membranes (Adamson et al., 1993, 1994; Coulam et al., 1993a, b; Kent et al., 1993; Zicari et al., 1995).

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Neonatal sequelae White matter lesions/cerebral palsy. There is considerable epidemiological evidence that prenatal exposure to infection increases the risk of neonatal brain damage (see review by Dammann and Leviton, 1997). It has been proposed that this susceptibility is, at least in part, the result of elevated cytokine production and action induced by infection. While the evidence for a role of cytokines in neonatal brain damage is largely indirect, the argument is logical and compelling. The incidence of cerebral palsy among infants born preterm and at very low birth weights has increased dramatically as improving neonatal intensive care has permitted more of these children to survive (Pharoah et al., 1990). Prematurity itself is associated with the development of white matter lesions and cerebral palsy; however, it appears that infectious complications of pregnancy, which may lead to preterm birth, also have a critical influence on development of brain damage. This has been demonstrated in two recent, well-performed studies. Murphy et al. (1995) examined a cohort of babies born at <32 weeks of gestation and, in addition to the expected association with gestational age, found an association between the development of cerebral palsy and several antenatal complications which may have resulted in fetal exposure to infection (prolonged rupture of the membranes, chorioamnionitis, and maternal infection). This association persisted following adjustment for gestational age and was particularly strong for chorioamnionitis, a condition that may indicate infection within the uterus. Similarly, Grether and Nelson (1997) studied children of normal birth weights and found an association between unexplained spastic cerebral palsy in those infants and placental infection (chorioamnionitis etc.) or maternal infection (fever, sepsis, etc.) during pregnancy. A more direct causal link between exposure to intrauterine infection and brain damage has been indicated by an animal study, in which experimentally induced intrauterine infection resulted in white matter lesions in fetal rabbits (Yoon et al., 1997a). As mentioned in preceding sections, concentrations of several cytokines increase in amniotic fluid and gestational tissues following infection/exposure to bacterial products. Elevations in white cell counts or in concentrations of several inflammatory cytokines and chemokines (IL-6, IL-1, IL-8) in the amniotic fluid have been determined to be risk factors for the development of white matter damage and cerebral palsy in infants (Yoon et al., 1997d, 2000). Elevated IL-6 in umbilical cord plasma, perhaps indicating a systemic inflammatory response in the fetus, is also associated with white matter damage in infants (Yoon et al., 1996). IL-1, TNF-
, and IL-6 have been shown to cross the blood-brain barrier in adult mice (Banks et al., 1993, 1994; Gutierrez, Banks and Kastin, 1993; Banks et al., 1991) and are also produced by microglial cells and astrocytes from fetal human brain (Lee et al., 1993a). Further, microglia and astrocytes respond to IL-1 and TNF-
with increased production of inflammatory cytokines and, in the case of microglia, M-CSF (Lee et al., 1993a, b). Examination of neonatal brain shows that immunoreactive TNF-
and IL-6 are more likely

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to be present in brain tissue (astrocytes and microglial cells) of infants with periventricular leukomalacia than in infants without this disorder (Yoon et al., 1997c; Deguchi et al., 1996). The mechanisms by which these cytokines might damage developing white matter have been reviewed by Dammann and Leviton (1997). Bronchopulmonary dysplasia. Bronchopulmonary dysplasia (BPD) is a chronic lung disease that is a frequent complication of prematurity, particularly in infants under mechanical ventilation. The inflammatory events associated with BPD have been reviewed by Pierce and Bancalari (1995) and Ozdemir et al. (1997). These include elevated cytokines (IL-8, IL-1, IL-6, and TGF-) and changes in cytokine ratios in lung lavage fluids during early postnatal life (Patterson et al., 1998; Pierce and Bancalari, 1995; Ozdemir et al., 1997). Elevated or decreased levels of additional cytokines (TNF-
, IL-10) have also been reported in later stages of BPD (Ozdemir et al., 1997). Development of bronchopulmonary dysplasia may be related to antenatal exposure to infection (Watterberg et al., 1996; Pierce and Bancalari, 1995). Chorioamnionitis and elevated concentrations of amniotic fluid IL-6, IL-1, and IL-8 are associated with an increased risk of BPD in the newborn (Yoon et al., 1997b; Ghezzi et al., 1998; Watterberg et al., 1996). It has been proposed that aspiration of amniotic fluid containing microorganisms and elevated inflammatory cytokines leads to a systemic fetal inflammatory response (Ghezzi et al., 1998). Such a response, characterized by elevated fetal plasma IL-6, is associated with severe neonatal morbidity (Gomez et al., 1998). A specific association with development of BPD has been noted for elevations in umbilical plasma IL-6 at birth (Yoon et al., 1999).

Viewpoint/Summary It is our contention that cytokines play a critical coordinating role in multiple biochemical and physiological mechanisms that regulate, and are associated with, pregnancy and parturition in women. Furthermore their actions (through changes in secretion rates, antagonist concentrations, receptor abundance, etc.) can be invoked early or aberrantly and can result in, or contribute to, several diseases of human pregnancy, such as preterm delivery and pre-eclampsia. Undoubtedly these facts contribute to and enhance the view that parturition may be likened to an inflammatory reaction/process (Mitchell et al., 1983), a comparison also used to describe the processes of ovulation (Espey, 1980) and cervical ripening (Liggins, 1981). However, the possibility also exists that abnormal cytokine secretion patterns may occur independent of any overt inflammatory trigger. The importance of cytokines to pregnancy and the parturient process may be illustrated by the subjugation of their usual activities to the cause of progression and acceleration of delivery. How else can we explain the reported pro-inflammatory actions of the normally anti-inflammatory glucocorticoids, interleukin-10, interleukin-4, and interleukin-1

Placenta (2002), Vol. 23

receptor antagonist under varying conditions in gestational/ uterine tissues (Adamson et al., 1993, 1994; Mitchell et al., 1993a; Simpson et al., 1999). Clearly the drive to accelerate and complete the process of labour and delivery has primacy in this environment, and evolution has adapted and modified the actions of immunological regulatory molecules to fulfill a different purpose in pregnancy. The exciting inference from such a view is that as we come to understand the complexities of the system we may find ways to modify and overcome undesirable outcomes whilst maximizing the positive/beneficial effects. Thus treatments may be based on using and enhancing women’s own natural regulatory systems

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