A novel role for GSK3 in the regulation of the processes of human labour

Abstract

Preterm birth remains the largest single cause of neonatal death and morbidity. Infection and/or inflammation are strongly associated with preterm delivery. Glycogen synthase kinase 3 (GSK3) is known to be a crucial mediator of inflammation homeostasis. The aims of this study were to determine the effect of spontaneous human labour in foetal membranes and myometrium on GSK3a/b expression, and the effect of inhibition of GSK3a/b on pro-labour mediators in foetal membranes and myometrium stimulated with Toll-like receptor (TLR) ligands and pro-inflammatory cytokines. Term and preterm labour in foetal membranes was associated with significantly decreased serine phosphorylated GSK3a and b expression, and thus increased GSK3 activity. There was no effect of term labour on serine phosphorylated GSK3b expression in myometrium. The specific GSK3a/b inhibitor CHIR99021 significantly decreased lipopolysaccharide (ligand to TLR4)-stimulated pro-inflammatory cytokine gene expression and release; COX2 gene expression and prostaglandin release; and MMP9 gene expression and pro MMP9 release in foetal membranes and/or myometrium. CHIR99021 also decreased FSL1 (TLR2 ligand) and flagellin (TLR5 ligand)-induced pro-inflammatory cytokine gene expression and release and COX2 mRNA expression and prostaglandin release. GSK3b siRNA knockdown in primary myometrial cells was associated with a significant decrease in IL1b and TNFa-induced pro-inflammatory cytokine and prostaglandin release. In conclusion, GSK3a/b activity is increased in foetal membranes after term and preterm labour. Pharmacological blockade of the kinase GSK3 markedly reduced pro-inflammatory and pro-labour mediators in human foetal membranes and myometrium, providing a possible therapeutics for the management of preterm labour.

Fetal membrane architecture, aging and inflammation in pregnancy and parturition

“…Glycogen synthase kinase 3 (GSK3) activity is increased in fetal membranes after term and preterm labour [51]. In fetal membranes, the GSK3 inhibitor CHIR99021 significantly attenuated TNF-α, IL-1β, IL-6 and IL-8 mRNA expression and secretion induced by the bacterial products and TLR ligands LPS (TLR4 ligand), fsl-1 (TLR2/6 ligand) and flagellin (TLR5 ligand) [51]. The involvement of GSK3 as a regulator of inflammation makes inhibition of GSK3 using synthetic compounds an attractive avenue of research.…”

Function and failure of the fetal membrane: Modelling the mechanics of the chorion and amnion

“…It has thus been proposed that this represents a “programmed weakening” or “pre-weakening” of the fetal membrane such that it ruptures in the correct area at term, although the mechanical behaviour and failure of this region in vivo remains to be determined. Indeed, a recent review of the current understanding highlighted a cascade of biochemical signalling and expression that leads to “pre-weakening” and can be affected by pro-inflammatory signalling [23–25], developing into a “weak zone” above the cervix from which fetal membrane rupture initiates [8]. …”

p38 Mitogen activated protein kinase (MAPK): a new therapeutic target for reducing the risk of adverse pregnancy outcomes

“…These drugs are primarily inhibitors of inflammatory pathway. Their targets included inhibition of NF-κB [55–58], enhancers of antiinflammatory peroxisome proliferator activated receptor (PPARs) [59], and antioxidant N-acetyl cysteine[60,61], cytokine suppressive anti-inflammatory drugs [62,63], agents to regulate Glycogen synthase kinase 3 (GSK3), an enzyme crucial for inflammation homeostasis [64], surfactant protein-A and PGJ2 to down regulate TLR mediated inflammation [65,66], targeted IL-6[67], and IL-1β signaling [68] to reduce inflammation, over antiinflammatory suppression using IL-10[69–71]. Although many of these (drugs) agents were successful in reducing inflammation or oxidative stress in vitro, some of them were shown to have toxic side effects in animal model trials or in clinical trials, and successful clinical trial outcomes are thus yet to be reported using any of these agents in reducing the risk of PTB.…”