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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

Authors

  • Ratana Lim,

    1. Obstetrics, Nutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, University of Melbourne, Heidelberg, Vic., Australia
    2. Mercy Perinatal Research Centre, Mercy Hospital for Women, Heidelberg, Vic, Australia
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  • Gillian Barker,

    1. Obstetrics, Nutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, University of Melbourne, Heidelberg, Vic., Australia
    2. Mercy Perinatal Research Centre, Mercy Hospital for Women, Heidelberg, Vic, Australia
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  • Martha Lappas

    Corresponding author
    1. Obstetrics, Nutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, University of Melbourne, Heidelberg, Vic., Australia
    2. Mercy Perinatal Research Centre, Mercy Hospital for Women, Heidelberg, Vic, Australia
    • Correspondence

      Martha Lappas, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, Level 4/163 Studley Road, Heidelberg 3084, Vic., Australia.

      E-mail: mlappas@unimelb.edu.au

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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.

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