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

Geurts, J. and van den Brand, B. T. and Wolf, A. and Abdollahi-Roodsaz, S. and Arntz, O. J. and Kracht, M. and van den Berg, W. B. and van de Loo, F. A.. (2011) Toll-like receptor 4 signalling is specifically TGF-beta-activated kinase 1 independent in synovial fibroblasts. Rheumatology, 50 (7). pp. 1216-1225.

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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-beta-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-1beta and IL-6) and chemokines (IL-8 and MCP-1). RESULTS: TAK1 inhibition abrogated cytokine- and TLR-induced nuclear factor-kappaB (NF-kappaB) and Saa3-promoter reporter activation in murine and human dermal fibroblasts. In synovial fibroblasts, TAK1 regulated IL-1 and TNF-mediated NF-kappaB, 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-kappaB reporter activation and inducible mRNA expression was fully TAK1 independent. Accordingly, NF-kappaB 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.
Faculties and Departments:03 Faculty of Medicine > Bereich Operative Fächer (Klinik) > Ehemalige Einheiten Operative Fächer (Klinik) > Orthopädie (Valderrabano)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Operative Fächer (Klinik) > Ehemalige Einheiten Operative Fächer (Klinik) > Orthopädie (Valderrabano)
UniBasel Contributors:Geurts, Jeroen
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Oxford University Press
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:04 Oct 2017 15:03
Deposited On:04 Oct 2017 15:03

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