Pro-inflammatory mediators and spontaneous preterm labour
Inflammation plays a crucial role in the process of parturition(11,62). Most conditions that lead to spontaneous preterm labour are associated with preterm premature rupture of membranes (PPROM). In preterm labour, pathological mechanisms involving the cervix, foetus, foetal membranes, placenta, and myometrium activate prematurely one or more of the components of the pathway of parturition(62). During preterm labour, uterine activity is changed from a state of quiescence to a pro-inflammatory milieu in a three-step process characterized by uterine contractility, cervical remodelling and membrane activation/rupture which is modulated by pro-inflammatory mediators/cytokines(11,62,63). Intrauterine infection is one of the most frequent conditions leading to preterm labour and the pathogenic mechanisms are related to activation of receptors (toll-like receptors) on the innate immune system(62). The significant components of the innate immune system are pattern recognition receptors. Toll-like receptors (TLRs) are a class of pattern recognition receptors that detect pathogen-associated molecular patterns (PAMPS) derived from microorganisms and damage-associated molecular patterns (DAMPS) released from immune cells, stressed and dying cells. This stimulates intracellular signalling cascades leading to the expression of pro-inflammatory mediators/cytokines by innate immune cells resulting in normal or preterm labour (figure 3) (64,65).
Pro-inflammatory mediators are structurally classified into 4 groups: the 4α helix family members - interleukin 2 (IL-2), interferon gamma (IFN-γ) and IL-10; IL-1 family; IL-17 family; and chemokines. Functionally, these pro-inflammatory mediators/cytokines are grouped into T helper type 1 (Th1) cell reactions (cell-mediated immunity) and T helper type 2 (Th2) reactions (humoral immunity)(62). Inflammatory cytokines are produced by T Lymphocytes (CD4+) which modulate immune response to inflammatory stimuli. Primarily, Th1 cells produce IL-1, IL-2, IL-6, IL-12, IL-15, IL-18, IFN-γ, and tumor necrosis factor alpha (TNF-α) and Th2-cells produce IL-4, IL-5, IL-10, IL-13, and granulocyte macrophage colony stimulating factor (GM-CSF)(62,66).
The presence of intrauterine infection causes infiltration of circulating monocytes and neutrophils into the myometrium and cervix leading to significant gene expression for interleukins (IL-1β, IL-6, IL-8) and Tumour Necrosis Factor alpha (TNF-α )(11,62). Myometrial contractions are stimulated by the increase of IL-1 and TNF-α which promote influx of calcium into myometrial smooth muscle cells(11,67). Pro-inflammatory mediators also cause increased gene expression for prostaglandin synthase coupled with cyclooxygenase-2 gene expression leading to up-regulation of prostaglandins and collagenases in uterine tissues and cervix (65). Prostaglandins, PGF2 and PGE2 are also involved in the stimulation of myometrial contractions and cervical ripening(68–70). Cervical shortening and softening is due to the progressive increased in the amount of hyaluronidase and other enzymes that break down the glycosaminoglycans (GAGS) while collagenases break down the cervical collagen. This leads to increased water absorption by the cervix. IL-4, IL-5, IL-10 and IL-13 produced by Th2-cells play a rather potential protective role in the feto-maternal relationship and prevent preterm labour (figure 3)(62).
In early stage of inflammation, activation and maturation of neutrophils and macrophages occur by stimulatory effect of pro-inflammatory cytokine such as IL-6 in addition to increased differentiation of natural killer cells resulting in invasion of the cervical and endometrial tissue with subsequent stimulatory effect on the uterine contractility(71). Similarly, IL-6 causes increased oxytocin receptors expression on myometrial cells with further enhancement of their responsiveness to oxytocin. In another pathway, IL-6 causes increased production of prostaglandins from activation of the hypothalamic-pituitary-adrenal axis and this result in initiation of uterine contraction and progressive cervical dilatation(72).
Pro-inflammatory mediators also stimulate matrix metalloproteinases (MMPs) such as collagenase, gelatinase and stromelysin, hyaluronidases and prostaglandins expression which promote extracellular matrix degradation, uterine contractions and cervical ripening leading to preterm labour (figure 3)(47,62,73,74). Major proteinases associated with this mechanism are collagenases: 1, 2, 3 and 4, also known as MMP-1, MMP-8, MMP-13 and MMP-18; gelatinases A and B (MMP-2 and MMP-9, respectively); and stromelysin-1 (MMP-3) and stromelysin-2 (MMP-10) are normally expressed during labour(47,75).