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).