Inflammatory processes in preterm and term parturition

doi:10.1016/j.jri.2008.04.002

Journal of Reproductive Immunology

Volume 79, Issue 1, October 2008, Pages 50-57

https://doi.org/10.1016/j.jri.2008.04.002 Get rights and content

Abstract

A role for the pro-inflammatory cytokines interleukin (IL)-1β, IL-6, IL-8 and tumor necrosis factor alpha (TNF-α) is evident in term and preterm delivery, and this is independent of the presence of infection. All uterine tissues progress through a staged transformation near the end of pregnancy that leads from relative uterine quiescence and maintenance of pregnancy to the activation of the uterus that prepares it for the work of labour and production of stimulatory molecules that trigger the onset of labour and delivery. The uterus is activated by pro-inflammatory cytokines through stimulation of the expression and production of uterine activation proteins (UAPs). One of these actions is the stimulation of prostaglandin (PG) synthesis. Particularly important for labour is PGF_2α and its receptor, PTGFR. In addition, pro-inflammatory cytokines are able to increase the synthesis of matrix metalloproteinases (MMPs), vascular endothelial growth factor (VEGF) and the progesterone receptor C isoform, which leads to decreased tissue progesterone responsiveness. Some of these effects are replicated by PGF_2α, suggesting that it may act via its receptor to amplify the direct actions of cytokines. In turn, VEGF may enhance leukocyte recruitment to the uterus, and MMP-9 may promote activation of inactive pro-form cytokines. Pro-inflammatory cytokines also decrease the activity of 11β-hydroxysteroid dehydrogenase, which likely increases intrauterine cortisol concentrations. In turn, cortisol may drive PG synthesis. Together these feed-forward mechanisms activate the uterus, trigger the production of uterine contractile stimulants and lead to labour and delivery.

Introduction

Preterm birth (<37 weeks of gestation) is the leading cause of mortality and morbidity in newborn infants. Data from the Canadian Perinatal Surveillance Report show that 81.6% of infants born preterm have a low birth weight (LBW; <2500 g at birth) and that 60% of all neonatal deaths occur among LBW and preterm infants (Health-Canada, 1999). Further, preterm birth and LBW are associated with high neonatal and infant morbidity, including chronic respiratory illnesses, neurodevelopmental problems and long-term impairment (Berkowitz and Papiernik, 1993, Kramer, 1987).

Currently, over 60% of preterm deliveries are unexplained (Green et al., 2005), ascribable only to ‘idiopathic’ preterm labour or preterm premature rupture of fetal membranes. Some experts believe that these are associated with a (sub)clinical inflammatory response in the maternal and/or fetal tissues. Shim et al. (2004) showed that up to 70% of spontaneous preterm birth <30 weeks of gestation is associated with intrauterine infection, compared to only 30–40% after 30 weeks. Bacterial vaginosis alone or progression to chorioamnionitis are important risk factors for preterm birth (Leitich et al., 2003). Various sexually transmitted diseases, such as gonorrhoea and syphilis, are also associated with an increased risk of a preterm delivery (Goldenberg et al., 1997). This is true also for periodontal disease (Goepfert et al., 2004), data that strongly implicate inflammatory processes in the genesis of preterm birth.

Pregnancies that display signs of infection are characterized by elevated levels of pro-inflammatory cytokines, including interleukin (IL)-1β, IL-6, IL-8 and tumor necrosis factor alpha (TNF-α), in the amniotic fluid, myometrium, decidua, fetal membranes and maternal serum (Goldenberg et al., 2000). Pregnancies without signs of infection in the third trimester and deliveries without infection also show increased levels of IL-1β and IL-8 in the amnion, chorio-decidua and myometrium (Elliott et al., 2001). This suggests a causal role for cytokines in the process of parturition, regardless of the presence of infection.

Parturition involves five distinct yet integrated physiological events: rupture of the membranes, cervical ripening and dilatation, contractility of the myometrium, placental separation and uterine involution (Olson, 2003). Prostaglandins (PGs), produced by the myometrium and intrauterine tissues of pregnancy, are involved in all these events. Most commonly, PGs are associated with stimulation of the myometrium. Indeed, treatment of pregnant women with PGs induces labour. Furthermore, inhibitors of PG endoperoxide H synthase (PGHS) delay the time of onset of labour (Novy et al., 1974).

The most potent uterine contractile prostanoid is PGF_2α, and its action is mediated by its specific receptor, PTGFR (Olson, 2005). PTGFR is a key uterine activation protein (UAP), promoting the ability of the tissues to carry out the process of parturition. Myometrial PTGFR mRNA is elevated at term and preterm birth in humans and rodents (Brodt-Eppley and Myatt, 1999, Cook et al., 2003). Also, infusion of a specific inhibitor, THG113.31, in sheep and mice delays preterm birth and prolongs gestation (Hirst et al., 2005, Peri et al., 2002). In rats, myometrial PTGFR mRNA expression rate is decreased during pregnancy, and its expression increases significantly again at term (Matsumoto et al., 1997). This suggests that PTGFR plays a central role in both pregnancy maintenance and parturition.

The purpose of this review is to describe the relationships between pro-inflammatory cytokines, PGF_2α and PTGFR and uterine activation during normal term pregnancy and at preterm birth.

Section snippets

Uterine pro-inflammatory cytokines

Interleukin-1β, IL-6 and TNF-α are pleiotropic cytokines in terms of being produced by and eliciting a response from a myriad of cells, many of which are autocrine (Lucey et al., 1996). They are also pleiotropic in eliciting a number of different cellular responses (e.g. TNF-α stimulates both survival and apoptosis) (Baker and Reddy, 1998). However, all three stimulate translocation of the transcription factor, nuclear factor kappa B (NFκB), to the nucleus and subsequent triggering of

The effect of cytokines on prostaglandin synthesis and uterine activation

There is strong evidence in all species supporting an essential role for PGs in parturition; hence, their synthesis, metabolism and actions are of importance (Olson, 2003, Olson, 2005). The key regulatory steps in PG synthesis revolve around the release of the precursor, arachidonic acid, from membrane phospholipids and its conversion to an endoperoxide intermediate by PGHS. Two isoforms of the PGHS enzyme exist: PGHS-1 is expressed in many tissues and is responsible for constitutive PG

Cytokines stimulate uterine activation via the NFκB system

The NFκB family of transcription factors is associated with inflammation and can be activated by pro-inflammatory cytokines. Considerable evidence accumulated since 1999 has shown that NFκB is involved with many aspects of PG synthesis and action in intrauterine tissues, especially in association with labour. This mechanism includes stimulation by TNF-α, IL-1β and LPS (Belt et al., 1999, Lappas et al., 2006). It appears that NFκB mediates IL-1β action at several levels of the PG

Cytokines, intrauterine cortisol and prostaglandins

Interconversion of the active glucocorticoid cortisol and its inactive metabolite cortisone is catalyzed by 11β-hydroxysteroid dehydrogenase (11β-HSD). There are two isoforms of this enzyme (Albiston et al., 1994): 11β-HSD1, which has low affinity for cortisol, is widely distributed, operates bidirectionally and requires NADP(H) as a co-factor; and 11β-HSD2, which is a high affinity, unidirectional oxidase and is NAD⁺-dependent. Human placental 11β-HSD activity is essentially entirely due to

Prostaglandins and MMPs in the uterus

The matrix metalloproteinases, MMP-2 and -9, increase in decidua and other intrauterine tissues at term (Goldman et al., 2003), possibly because of a loss of progesterone activity (Goldman and Shalev, 2006). MMP-1, -2, -3 and -9 further degrade released IL-1β (but not IL-1α) into inactive forms (Ito et al., 1996). Taken together, these data indicate the complexity of responses to IL-6, TNF-α and IL-1β, especially in the decidua where proteases are activated during parturition (Tsatas et al.,

Cytokines, prostaglandins and the progesterone receptor

Two principal progesterone receptor forms exist. The PR-A (94 kDa) is an N-terminally truncated form of PR-B (116 kDa) (Vegeto et al., 1993). PR-A is a weaker activator of transcription than PR-B, and PR-A can act as a transrepressor of PR-B (Pieber et al., 2001). The cellular response to progesterone is dependent upon the levels and ratios of PR-A and PR-B. In co-transfection studies in amnion, increasing PR-A relative to PR-B led to an inhibition of PR-B-mediated transcription. A third isoform,

Summary and future directions

Convincing data support a role for cytokines in mechanisms that maintain and terminate normal pregnancy. It is evident that increased levels of cytokines are associated with term parturition, that inhibition of their synthesis or action attenuates their effects and delays induced or term parturition, and preterm activation of inflammatory cells and production of cytokines or exogenous administration of cytokines frequently leads to preterm birth. Their actions often affect processes of

Acknowledgements

These studies were supported by funding from the Canadian Institutes of Health Research and from the Alberta Heritage Foundation for Medical Research Interdisciplinary Team in Preterm Birth and Healthy Outcomes. Dr. Christiaens is a recipient of a CIHR Strategic Training Program in Maternal-Fetal-Newborn Health award from the Institute of Human Development, Child and Youth Health.

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Review articleInflammatory processes in preterm and term parturition

Abstract

Introduction

Section snippets

Uterine pro-inflammatory cytokines

The effect of cytokines on prostaglandin synthesis and uterine activation

Cytokines stimulate uterine activation via the NFκB system

Cytokines, intrauterine cortisol and prostaglandins

Prostaglandins and MMPs in the uterus

Cytokines, prostaglandins and the progesterone receptor

Summary and future directions

Acknowledgements

Surgery

Am. J. Obstet. Gynecol.

Obstet. Gynecol.

Am. J. Obstet. Gynecol.

Clin. Perinatol.

Am. J. Obstet. Gynecol.

Am. J. Obstet. Gynecol.

Am. J. Obstet. Gynecol.

J. Biol. Chem.

Am. J. Obstet. Gynecol.

Placenta

Am. J. Obstet. Gynecol.

Mol. Cell

Am. J. Obstet. Gynecol.

Biochem. Biophys. Res. Commun.

Am. J. Obstet. Gynecol.

Semin. Neonatol.

Am. J. Obstet. Gynecol.

Best Pract. Res. Clin. Obstet. Gynaecol.

Semin. Perinatol.

Am. J. Obstet. Gynecol.

Eur. J. Pharmacol.

J. Reprod. Immunol.

Am. J. Obstet. Gynecol.

J. Steroid Biochem. Mol. Biol.

Placenta

Biochim. Biophys. Acta

J. Invest. Dermatol.

Cloning and tissue distribution of the human 11 beta-hydroxysteroid dehydrogenase type 2 enzyme

Mol. Cell. Endocrinol.

Contribution of TNF-alpha converting enzyme and proteinase-3 to TNF-alpha processing in human alveolar macrophages

Am. J. Respir. Cell. Mol. Biol.

Modulation of life and death by the TNF receptor superfamily

Oncogene

Epidemiology of preterm birth

Epidemiol. Rev.

Soluble TNF and membrane TNF expressed on CD4+ T lymphocytes differ in their ability to activate macrophage antileishmanial defense

J. Leukoc. Biol.

Tumour necrosis factor-alpha stimulates expression of TNF-alpha converting enzyme in endothelial cells

Eur. J. Biochem.

Up-regulation of the progesterone receptor (PR)-C isoform in laboring myometrium by activation of nuclear factor-kappaB may contribute to the onset of labor through inhibition of PR function

Mol. Endocrinol.

Surfactant protein secreted by the maturing mouse fetal lung acts as a hormone that signals the initiation of parturition

Proc. Natl. Acad. Sci. U.S.A.

Mouse placental prostaglandins are associated with uterine activation and the timing of birth

Biol. Reprod.

Pregnancy and exogenous steroid treatments modulate the expression of relaxant EP(2) and contractile FP receptors in the rat uterus

Biol. Reprod.

Review article
Inflammatory processes in preterm and term parturition