title: The TLR2 ligand FSL-1 and the TLR5 ligand Flagellin mediate pro-inflammatory and pro-labour response via MyD88/TRAF6/NF-κB-dependent signalling.
abstract: OBJECTIVE
  Toll-like receptors (TLRs) 2 and 5 induce inflammation via the adapter proteins myeloid differentiation factor 88 (MyD88) and TNFR-associated factor 6 (TRAF6) and the transcription factor nuclear factor-kappa B (NF-κB). The aims of this study were to determine the effects of the TLR5 ligand flagellin and the TLR2 ligand FSL-1 on pro-inflammatory and pro-labour mediators in human fetal membranes and myometrium, and to establish whether their actions are dependent on MyD88, TRAF6 and NF-κB.
  
  
  METHODS
  Tissue explants were performed to determine the effect of flagellin and FSL-1 on pro-labour mediators in fetal membranes and myometrium. siRNA knockdown was performed in primary amnion and myometrium cells to determine the role of MyD88, TRAF6 and NF-κB.
  
  
  RESULTS
  Flagellin and FSL-1 increased pro-inflammatory cytokines (IL-6 and IL-8), MMP-9 expression and activity, and COX-2 expression and prostaglandin release. siRNA knockdown of TLR2 decreased FSL-1 induced production of IL-6, IL-8, COX-2, prostaglandins and MMP-9; similarly, siRNA knockdown of TLR5 decreased flagellin induced production of these pro-labour mediators. The effects of flagellin and FSL-1 are mediated by MyD88 and TRAF6, as siRNA knockdown of MyD88 and TRAF6 decreased flagellin and FSL-1 induced pro-labour mediators. Additionally, the effects of flagellin and FSL-1 are mediated via NF-κB, as flagellin and FSL-1 increased NF-κB transcriptional activity, and the NF-κB inhibitor BAY 11-7082 attenuated flagellin and FSL-1 induced expression and secretion of pro-labour mediators.
  
  
  CONCLUSIONS
  TLR2 engagement by the synthetic lipoprotein FSL-1 and TLR5 engagement by bacterial flagellin enhances pro-inflammatory and pro-labour mediators in human fetal membranes and myometrium via MyD88/TRAF6/NF-κB.
authors.affiliation: Obstetrics, Nutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, University of Melbourne, Heidelberg, Vic., Australia; Mercy Perinatal Research Centre, Mercy Hospital for Women, Heidelberg, Vic, Australia.
authors.forename: Ratana
authors.initials: R
authors.lastname: Lim
authors.forename: Gillian
authors.initials: G
authors.lastname: Barker
authors.forename: Martha
authors.initials: M
authors.lastname: Lappas
mesh_terms: D051546:Cyclooxygenase 2; D004075:Diglycerides / Q000494:pharmacology*; D005321:Extraembryonic Membranes / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005333:Fetus; D005408:Flagellin / Q000494:pharmacology*; D005786:Gene Expression Regulation; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics* / Q000378:metabolism; D009215:Myometrium / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology*; D011247:Pregnancy; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013450:Sulfones / Q000494:pharmacology; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics* / Q000378:metabolism; D046509:Tissue Culture Techniques; D051195:Toll-Like Receptor 2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D051198:Toll-Like Receptor 5 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D004075:Diglycerides; C460864:FSL-1 lipoprotein, synthetic; C508600:IL6 protein, human; D015850:Interleukin-6; D016209:Interleukin-8; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D009570:Nitriles; D009842:Oligopeptides; D034741:RNA, Small Interfering; D013450:Sulfones; C495342:TLR2 protein, human; C495346:TLR5 protein, human; D048029:TNF Receptor-Associated Factor 6; D051195:Toll-Like Receptor 2; D051198:Toll-Like Receptor 5; D005408:Flagellin; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9
keywords: Foetal membranes; MyD88; NFkappa B; TLR2; TLR5; myometrium