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The aims of this study were to determine the effect of spontaneous human labour in foetal membranes and myometrium on GSK3\u03b1\/\u03b2 expression, and the effect of inhibition of GSK3\u03b1\/\u03b2 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 GSK3\u03b1 and \u03b2 expression, and thus increased GSK3 activity. There was no effect of term labour on serine phosphorylated GSK3\u03b2 expression in myometrium. The specific GSK3\u03b1\/\u03b2 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. GSK3\u03b2 siRNA knockdown in primary myometrial cells was associated with a significant decrease in IL1\u03b2 and TNF\u03b1-induced pro-inflammatory cytokine and prostaglandin release. In conclusion, GSK3\u03b1\/\u03b2 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.<\/jats:p>","DOI":"10.1530\/rep-14-0493","type":"journal-article","created":{"date-parts":[[2014,12,30]],"date-time":"2014-12-30T23:58:33Z","timestamp":1419983913000},"page":"189-202","update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-1","source":"Crossref","is-referenced-by-count":13,"title":["A novel role for GSK3 in the regulation of the processes of human labour"],"prefix":"10.1093","volume":"149","author":[{"given":"Ratana","family":"Lim","sequence":"first","affiliation":[{"name":"Mercy Perinatal Research Centre Mercy Hospital for Women, Heidelberg, Victoria, Australia 2 Nutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, University of Melbourne, Level 4\/163 Studley Road, Heidelberg, Victoria 3084, Australia"},{"name":"Obstetrics Mercy Hospital for Women, Heidelberg, Victoria, Australia 2 Nutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, University of Melbourne, Level 4\/163 Studley Road, Heidelberg, Victoria 3084, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martha","family":"Lappas","sequence":"additional","affiliation":[{"name":"Mercy Perinatal Research Centre Mercy Hospital for Women, Heidelberg, Victoria, Australia 2 Nutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, University of Melbourne, Level 4\/163 Studley Road, Heidelberg, Victoria 3084, Australia"},{"name":"Obstetrics Mercy Hospital for Women, Heidelberg, Victoria, Australia 2 Nutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, University of Melbourne, Level 4\/163 Studley Road, Heidelberg, Victoria 3084, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2015,2,1]]},"reference":[{"key":"2026010712405320600_bib1","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1097\/01.qco.0000224825.57976.87","article-title":"Neonatal infection and long-term neurodevelopmental outcome in the preterm infant","volume":"19","author":"Adams-Chapman","year":"2006","journal-title":"Current Opinion in Infectious Diseases"},{"key":"2026010712405320600_bib2","doi-asserted-by":"crossref","first-page":"1662","DOI":"10.1038\/ncomms2677","article-title":"FBXW7\u03b1 attenuates inflammatory signalling by downregulating C\/EBP\u03b4 and its target gene Tlr4","volume":"4","author":"Balamurugan","year":"2013","journal-title":"Nature Communications"},{"key":"2026010712405320600_bib3","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.ejphar.2011.01.060","article-title":"Tumor necrosis factor-\u03b1 induces increased lung vascular permeability: a role for GSK3\u03b1\/\u03b2","volume":"657","author":"Barton-Pai","year":"2011","journal-title":"European Journal of Pharmacology"},{"key":"2026010712405320600_bib4","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.it.2009.09.007","article-title":"Innate and adaptive immune responses regulated by glycogen synthase kinase-3 (GSK3)","volume":"31","author":"Beurel","year":"2010","journal-title":"Trends in Immunology"},{"key":"2026010712405320600_bib5","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1053\/plac.2001.0781","article-title":"Cytokines of the placenta and extra-placental membranes: biosynthesis, secretion and roles in establishment of pregnancy in women","volume":"23","author":"Bowen","year":"2002","journal-title":"Placenta"},{"key":"2026010712405320600_bib6","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.jri.2008.04.002","article-title":"Inflammatory processes in preterm and term parturition","volume":"79","author":"Christiaens","year":"2008","journal-title":"Journal of Reproductive Immunology"},{"key":"2026010712405320600_bib8","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1038\/nrd1415","article-title":"GSK3 inhibitors: development and therapeutic potential","volume":"3","author":"Cohen","year":"2004","journal-title":"Nature Reviews. 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