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

作者：Geurts Jeroen; van den Brand Ben T; Wolf Alexander; Abdollahi Roodsaz Shahla; Arntz Onno J; Kracht Michael; van den Berg Wim B; van de Loo Fons A J^*

来源：Rheumatology, 2011, 50(7): 1216-1225.

DOI：10.1093/rheumatology/ker021

• TGF-beta-activated kinase 1
• Signal transduction
• Synovial fibroblast
• Transcriptional reporter
• Toll-like receptor
• Nuclear factor-kappa B
• Rheumatoid arthritis

Methods. 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-1 beta and IL-6) and chemokines (IL-8 and MCP-1).
Results. TAK1 inhibition abrogated cytokine- and TLR-induced nuclear factor-kappa B (NF-kappa B) and Saa3-promoter reporter activation in murine and human dermal fibroblasts. In synovial fibroblasts, TAK1 regulated IL-1 and TNF-mediated NF-kappa B, 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-kappa B reporter activation and inducible mRNA expression was fully TAK1 independent. Accordingly, NF-kappa B p65 and p38 MAPK phosphorylation was unaffected by TAK1 inhibition.
Conclusion. 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.

• 出版日期2011-7