Toll-like receptors and mechanism of human parturition.
MSc(R) thesis, University of Glasgow.
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The process of parturition whether physiological at term or pathological in preterm labour is a complex one driven by fetal, placental and maternal signals. There is compelling evidence to suggest that inflammatory mediators, driven by endogenous factors or pathologically by infection, play a crucial role in stimulating the common parturition pathway leading into cervical ripening, uterine contractions and, finally, expulsion of the foetus and placenta.
Toll-like receptors (TLRs) are a relatively recently discovered family of pattern recognition molecules which have been shown to play a pivotal role in innate immune responses and inflammation. Products of micro-organisms, e.g. bacteria, viruses or fungi, can be considered to be primary ligands of Toll-like receptors. In addition, they are also activated by other endogenous ligands such as heat shock protein 60 and 70, extra domain A of fibronectin and surfactant protein A (SPA). Therefore, local activation of Toll-like receptors may be responsible for initiation of inflammatory cascade, in presence or absence of infection, leading to initiation of labouring mechanisms within the myometrium.
In this study, we hypothesized that Toll-like receptors (TLR 2 & 4) are expressed in labouring myometrium, and are involved in physiologic and pathophysiologic mechanisms of parturition. In order to test this hypothesis, we compared the pattern of expression of Toll-like receptors in myometrial samples obtained from consenting women before and after onset of term and preterm labour. We also aimed to investigate the activation, regulation of and the functional significance of TLR expression with respect to cytokine production in human myometrium at term, and to determine if progestogens could antagonise the effect of TLR ligands such as Lipopolysaccharide (LPS).
We identified the synthesis and presence of TLR2 & 4 in human myometrium as shown by expression of their mRNA and protein signals which appear to be increasing by gestation and
possibly by labour status. We also demonstrated a possible role for TLR2 as indicated by upregulation of its protein expression in labour compared with non-labouring myometrium. Although there was also a trend to an increase in TLR4 with labour, this did not reach statistical significance.
In our short-term tissue culture model, we demonstrated that Medroxyprogesterone acetate (MPA) significantly suppressed baseline and LPS induced production of IL-1β, IL-6 and IL-8 in pregnant human myometrium. Although LPS stimulated IL-10 production, there was no significant inhibitory effect with MPA. In contrast, we failed to demonstrate significant upregulation of either TNF-α or IFN-γ in response to LPS, and there was no effect of MPA. We also showed that the specific inhibitor for double stranded-RNA dependent protein kinase (PKR) 2-Aminopurine significantly inhibited both baseline and LPS stimulated myometrial cytokine production.
In conclusion, findings of this work have demonstrated a potential role for Toll-like receptors 2 & 4 in initiation of term and preterm labour and an anti-inflammatory role for the progestogen Medroxyprogestrone acetate in lipopolysaccahride stimulated myometrial tissue culture model in vitro. These findings highlight the need for further studies to examine the role of other progestogens / progesterone, benefits and risks to mothers and to their babies, in prevention of preterm labour.
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