التفاصيل البيبلوغرافية
| العنوان: |
Toll-like receptor 4 signalling is specifically TGF-beta-activated kinase 1 independent in synovial fibroblasts. |
| المؤلفون: |
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. |
| المصدر: |
Rheumatology; Jul2011, Vol. 50 Issue 7, p1216-1225, 10p, 5 Graphs |
| مصطلحات موضوعية: |
ANALYSIS of variance, ANIMAL experimentation, BIOPSY, COMPUTER software, ELECTROPHYSIOLOGY, FIBROBLASTS, METABOLISM, MICE, POLYMERASE chain reaction, RESEARCH funding, RHEUMATOID arthritis, STATISTICS, SYNOVIAL membranes, WESTERN immunoblotting, DATA analysis, EQUIPMENT & supplies, CASE-control method, REVERSE transcriptase polymerase chain reaction |
| مصطلحات جغرافية: |
GERMANY, NETHERLANDS |
| مستخلص: |
Objective. 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.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-1β and IL-6) and chemokines (IL-8 and MCP-1).Results. 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.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. [ABSTRACT FROM PUBLISHER] |
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| قاعدة البيانات: |
Complementary Index |
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