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.
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.
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).
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.
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