Toll-like receptor 4 signalling is specifically TGF-beta-activated kinase 1 independent in synovial fibroblasts.

Details

Serval ID
serval:BIB_1B70D0588B56
Type
Article: article from journal or magazin.
Publication sub-type
Minutes: analyse of a published work.
Collection
Publications
Title
Toll-like receptor 4 signalling is specifically TGF-beta-activated kinase 1 independent in synovial fibroblasts.
Journal
Rheumatology
Author(s)
Geurts J., van den Brand B.T., Wolf A., Abdollahi-Roodsaz S., Arntz O.J., Kracht M., van den Berg W.B., van de Loo F.A.
ISSN
1462-0332 (Electronic)
ISSN-L
1462-0324
Publication state
Published
Issued date
07/2011
Peer-reviewed
Oui
Volume
50
Number
7
Pages
1216-1225
Language
english
Notes
Publication types: Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
Activated synovial fibroblasts are key players in the pathogenesis of RA by driving inflammation and joint destruction. Numerous molecules including cytokines and Toll-like receptor (TLR) ligands induce pro-inflammatory signalling and gene expression through a hierarchical network of kinases. Upstream mitogen-activated protein kinase kinase kinases (MAP3Ks) represent an attractive target for RA treatment. In this study, we sought to determine the role of the MAP3K TGF-β-activated kinase 1 (TAK1) in cytokine and TLR-mediated signalling.
TAK1 activity was inhibited using either a small molecule inhibitor or lentivirally overexpressed kinase-inactive TAK1-K63W mutant in murine embryonic and human dermal and synovial fibroblasts. Fibroblasts were stimulated with IL-1, TNF, TLR2 or TLR4 agonists and responses were evaluated using transcriptional reporters, western blotting and analysis of gene expression of collagenases (MMP3 and MMP13), cytokines (IL-1β and IL-6) and chemokines (IL-8 and MCP-1).
TAK1 inhibition abrogated cytokine- and TLR-induced nuclear factor-κB (NF-κB) and Saa3-promoter reporter activation in murine and human dermal fibroblasts. In synovial fibroblasts, TAK1 regulated IL-1 and TNF-mediated NF-κB, but not Saa3-promoter reporter activation. Inducible mRNA expression of cytokines, collagenases and chemokines, except MCP-1, was TAK1 dependent for IL-1, TNF and TLR2 signalling. Unexpectedly, TLR4-mediated NF-κB reporter activation and inducible mRNA expression was fully TAK1 independent. Accordingly, NF-κB p65 and p38 MAPK phosphorylation was unaffected by TAK1 inhibition.
In general, TAK1 crucially regulates IL-1 and TNF signalling in fibroblasts. Interestingly, TLR4 signalling is specifically TAK1 independent in synovial fibroblasts. Consequently, therapeutic TAK1 inhibition in arthropathies may not dampen the damage-associated molecular pattern-mediated TLR4 activation of synovial fibroblasts.
Keywords
Analysis of Variance, Animals, Arthritis, Rheumatoid/metabolism, Blotting, Western, Cells, Cultured, Enzyme Activation, Female, Fibroblasts/cytology, Fibroblasts/metabolism, MAP Kinase Kinase Kinases/metabolism, Male, Mice, Mitogen-Activated Protein Kinase 1/metabolism, Reverse Transcriptase Polymerase Chain Reaction, Sensitivity and Specificity, Signal Transduction, Synovial Membrane/cytology, Synovial Membrane/metabolism, Toll-Like Receptor 4/analysis, Toll-Like Receptor 4/metabolism, Transforming Growth Factor beta1/metabolism
Pubmed
Web of science
Open Access
Yes
Create date
27/07/2020 18:00
Last modification date
28/07/2020 5:26
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