Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.


Toll-Like Receptor 4 Signalling Is Specifically TAK1-Independent in Synovial Fibroblasts.

van de Loo1,  Fons A. J., van den Brand1,  Ben T., Abdollahi-Roodsaz1,  Shahla, Arntz1,  Onno J., Kracht2,  Michael, Geurts1,  Jeroen, van den Berg1,  Wim B.

Department of Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Rudolf-Buchheim-Institute of Pharmacology, University of Giessen, Hannover, Germany

Introduction:

Activated synovial fibroblasts are key players in the pathogenesis of rheumatoid arthritis (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 transforming growth factor-b activated kinase1 (TAK1) in cytokine and TLR-mediated signalling.

Methods:

TAK1 activity was inhibited using either a small molecule inhibitor or lentivirallyoverexpressed 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 and analysis of gene expression of collagenases (MMP3,13), cytokines (IL-1b,-6) and chemokines (IL-8, MCP-1).

Results:

TAK1 inhibition abrogated cytokine- and TLR-induced activation of NF-kB and Saa3-promoter reporters in murine and human dermal fibroblasts. In synovial fibroblasts, TAK1 crucially regulated IL-1 and TNF-mediated NF-kB, but not Saa3-promoter activation.Furthermore, TAK1 was required for inducible mRNA expression of IL-1b, IL-6, IL-8, MMP3 and MMP13, but not MCP-1, in response to IL-1, TNF and TLR2 agonist. Unexpectedly, TLR4-induced NF-kB activation and gene expression was fully TAK1-independent.

Conclusion:

In general, TAK1 plays a prominent role in regulation of IL-1- and TNF mediated signalling in fibroblasts. Interestingly, TLR4 signalling is specifically TAK1-independent in synovial fibroblasts. Consequently, therapeutic TAK1 inhibition in arthropaties may not dampen the damage-associated molecular pattern-mediated TLR4 activation of synovial fibroblasts.

To cite this abstract, please use the following information:
van de Loo, Fons A. J., van den Brand, Ben T., Abdollahi-Roodsaz, Shahla, Arntz, Onno J., Kracht, Michael, Geurts, Jeroen, et al; Toll-Like Receptor 4 Signalling Is Specifically TAK1-Independent in Synovial Fibroblasts. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :1535
DOI: 10.1002/art.29301

Abstract Supplement

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