Cytokines and the Initiation of Parturition

Abstract

Rice 114 the inflammatory response. Most cytokines are pleiotropic, displaying functional plasticity and redundancy. They are involved in extensive, complex networks and may act synergistically as well as antagonistically in regulating target cell function. Human parturition displays many of the hallmarks of an inflammatory response, thus, the aim of this review is to consider the data available implicating cytokines in the initiation and/or progression of human parturition. To assess the putative involvement of cytokines in the process of human parturition an appreciation of their general biology is a requisite.Cytokines are low molecular weight polypeptides involved in the regulation of cell growth, activation and cell repair, immune responses, inflammation, hemopoiesis and fibrosis. Proteins classified as cytokines include interleukins (ILs), tumor necrosis factors (TNFs), interferons (IFNs), colony-stimulating factors (CSFs), erythropoietin, thrombopoietin and various other growth factors. This review focuses on the ILs and TNFs and their putative role in the proximal events involved in the initiation and/or progression of parturition. Interleukin-1: 2q14Structure Two functional forms of IL-1 (aka endogenous pyrogen, lymphocyte-activating factor), IL-1· (17 kD, 159 amino acids, pI = 5.0) and IL-1ß (17 kD, 153 amino acids, pI = 7.0) that are encoded by two different genes on chromosome 2 have been identified. The · and ß forms display approximately 27% homology, mainly restricted to the carboxy-terminal region, and their effects are mediated via the same receptor. IL-1s are synthesized as precursor molecules that are proteolytically cleaved to release mature peptides. The IL-1ß precursor can be cleaved by proteases including caspase-1, elastase, cathepsin G, and collagenase. ExpressionCells known to express IL-1· include:

Advanced glycation endproducts mediate pro-inflammatory actions in human gestational tissues via nuclear factor-κB and extracellular signal-regulated kinase 1/2

“…This effect may be both direct (through interaction with RAGE) and/or indirect, via generation of free oxygen radicals. This leads to the production of pro-inflammatory cytokines, growth factors, adhesion molecules and chemokines (Schmidt et al 1994, Hofmann et al 1999, Fiuza et al 2003, Shanmugan et al 2006) that have been implicated in the processes of human labour and delivery (Kniss 1999, Rice 2001, Bowen et al 2002. In isolated human first-trimester trophoblasts, AGE stimulates secretion of chemokines such as macrophage inflammatory protein (MIP)-1a and MIP-1b, induces apoptosis, and suppresses the secretion of human chorionic gonadotrophin, an effect that could be suppressed by inhibitors of NO synthases or the NF-kB pathway (Konishi et al 2004), thus suggesting that reactive nitrogen species as well as ROS contribute to AGE-mediated actions in the human gestational tissues.…”

“…Prostaglandins and pro-inflammatory cytokines, which are produced within the intrauterine environment, participate in the processes of human labour and delivery, specifically the regulation of myometrial contractility, cervical ripening and rupture of membranes (reviewed in Kniss 1999, Rice 2001 . Experimental data from cell culture, animal models and tissue studies have provided evidence that pro-inflammatory cytokines and prostaglandins accumulate in the amniotic fluid and intrauterine tissues of women at the time of labour at term, and they are elevated even further in infection-associated preterm labour.…”

“…Increased intrauterine cytokine and prostaglandin production, which occurs modestly with term labour, is a characterising feature of preterm labour, particularly in the presence of intrauterine infection (Kniss 1999, Rice 2001, Bowen et al 2002. Bacterial colonisation and/or inflammation of the choriodecidual interface induces production of pro-inflammatory cytokines that, in turn, lead to neutrophil activation and the synthesis and release of uterotonins such as prostaglandins, which cause uterine contractions, and metalloproteinases, that weaken fetal membranes and remodel cervical collagen (Rice 2001, Bowen et al 2002.…”

“…Bacterial colonisation and/or inflammation of the choriodecidual interface induces production of pro-inflammatory cytokines that, in turn, lead to neutrophil activation and the synthesis and release of uterotonins such as prostaglandins, which cause uterine contractions, and metalloproteinases, that weaken fetal membranes and remodel cervical collagen (Rice 2001, Bowen et al 2002. Recent evidence suggests that advanced glycation endproducts (AGE), which accumulate in diverse biological settings such as diabetes, aging and inflammation, exhibit immunomodulatory functions and therefore may be involved in many normal and abnormal physiological processes (Singh et al 2001, Ramasamy et al 2005.…”

Role of leptin in female reproduction

“…Leptin is a key modulator of the inflammatory and immune responses, preventing the embryo rejection by the maternal immune system [77] and regulating generation of arachidonic acid products, nitric oxide induction, and T cell cytokines [78], which play an important role in a number of normal and abnormal inflammatory processes, including the initiation and progression of human labor and delivery [108,109]. Thus, placental leptin may have a local autocrine immunomodulatory or anti-inflammatory role [110].…”