Toll-like receptor 4 signalling is specifically TGF-beta-activated kinase 1 independent in synovial fibroblasts.
Rheumatology (Oxford)
; 50(7): 1216-25, 2011 Jul.
Article
em En
| MEDLINE
| ID: mdl-21335610
ABSTRACT
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-ß-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-1ß 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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Membrana Sinovial
/
Proteína Quinase 1 Ativada por Mitógeno
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MAP Quinase Quinase Quinases
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Receptor 4 Toll-Like
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Fator de Crescimento Transformador beta1
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Fibroblastos
Tipo de estudo:
Diagnostic_studies
Limite:
Animals
Idioma:
En
Revista:
Rheumatology (Oxford)
Assunto da revista:
REUMATOLOGIA
Ano de publicação:
2011
Tipo de documento:
Article
País de afiliação:
Holanda