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The TLR2 Ligand FSL-1 and the TLR5 Ligand Flagellin Mediate Pro-Inflammatory and Pro-Labour Response via MyD88/TRAF6/NF-κB-dependent Signalling

The TLR2 Ligand FSL-1 and the TLR5 Ligand Flagellin Mediate Pro-Inflammatory and Pro-Labour Response via MyD88/TRAF6/NF-κB-dependent Signalling

Ratana Lim, Gillian Barker, Martha Lappas

Am J Reprod Immunol. 2014 May;71(5):401-17.

PMID: 24635133

Abstract:

Problem:
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.
Method of study:
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.
Conclusion:
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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP322455709	FSL-1		322455-70-9	Price

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