title: 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 GSK3α/β expression, and the effect of inhibition of GSK3α/β 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 GSK3α and β expression, and thus increased GSK3 activity. There was no effect of term labour on serine phosphorylated GSK3β expression in myometrium. The specific GSK3α/β 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. GSK3β siRNA knockdown in primary myometrial cells was associated with a significant decrease in IL1β and TNFα-induced pro-inflammatory cytokine and prostaglandin release. In conclusion, GSK3α/β 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.
authors.affiliation: Mercy Perinatal Research CentreMercy Hospital for Women, Heidelberg, Victoria, AustraliaObstetricsNutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, University of Melbourne, Level 4/163 Studley Road, Heidelberg, Victoria 3084, Australia Mercy Perinatal Research CentreMercy Hospital for Women, Heidelberg, Victoria, AustraliaObstetricsNutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, University of Melbourne, Level 4/163 Studley Road, Heidelberg, Victoria 3084, Australia.
authors.forename: Ratana
authors.initials: R
authors.lastname: Lim
authors.affiliation: Mercy Perinatal Research CentreMercy Hospital for Women, Heidelberg, Victoria, AustraliaObstetricsNutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, University of Melbourne, Level 4/163 Studley Road, Heidelberg, Victoria 3084, Australia Mercy Perinatal Research CentreMercy Hospital for Women, Heidelberg, Victoria, AustraliaObstetricsNutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, University of Melbourne, Level 4/163 Studley Road, Heidelberg, Victoria 3084, Australia mlappas@unimelb.edu.au.
authors.forename: Martha
authors.initials: M
authors.lastname: Lappas
mesh_terms: D005321:Extraembryonic Membranes / Q000201:enzymology / Q000502:physiology; D005260:Female; D015870:Gene Expression; D020868:Gene Silencing; D038362:Glycogen Synthase Kinase 3 / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007249:Inflammation / Q000517:prevention & control; D007743:Labor, Obstetric / Q000187:drug effects / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D009215:Myometrium / Q000201:enzymology / Q000502:physiology; D016328:NF-kappa B / Q000502:physiology; D011247:Pregnancy; D047928:Premature Birth / Q000201:enzymology / Q000517:prevention & control; D034741:RNA, Small Interfering / Q000235:genetics; D046509:Tissue Culture Techniques; D051193:Toll-Like Receptors / Q000502:physiology
chemical_list: D008070:Lipopolysaccharides; D016328:NF-kappa B; D034741:RNA, Small Interfering; D051193:Toll-Like Receptors; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha