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MyD88 and focal adhesion kinase (FAK) are key adaptors involved in signaling downstream of TLR2, TLR4, and integrin alpha5beta1, linking pathogen-associated molecule detection to the initiation of proinflammatory response. The MyD88 and integrin pathways are interlinked, but the mechanism of this cross-talk is not yet understood. In this study we addressed the involvement of Etk, which belongs to the Tec family of tyrosine kinases, in the cross-talk between the integrin/FAK and the MyD88 pathways in fibroblast-like synoviocytes (FLS) and in IL-6 synthesis. Using small interfering RNA blockade, we report that Etk plays a major role in LPS- and protein I/II (a model activator of FAK)-dependent IL-6 release by activated FLS. Etk is associated with MyD88, FAK, and Mal as shown by coimmunoprecipitation. Interestingly, knockdown of Mal appreciably inhibited IL-6 synthesis in response to LPS and protein I/II. Our results also indicate that LPS and protein I/II induced phosphorylation of Etk and Mal in rheumatoid arthritis FLS via a FAK-dependent pathway. In conclusion, our data provide support that, in FLS, Etk and Mal are implicated in the cross-talk between FAK and MyD88 and that their being brought into play is clearly dependent on FAK.

Original publication

DOI

10.4049/jimmunol.180.5.3485

Type

Journal article

Journal

J immunol

Publication Date

01/03/2008

Volume

180

Pages

3485 - 3491

Keywords

Agammaglobulinaemia Tyrosine Kinase, Bacterial Proteins, Cell Communication, Fibroblasts, Focal Adhesion Kinase 1, Humans, Integrin alpha5, Integrin beta1, Lymphocyte Activation, Membrane Transport Proteins, Multigene Family, Myelin Proteins, Myelin and Lymphocyte-Associated Proteolipid Proteins, Myeloid Differentiation Factor 88, Protein-Tyrosine Kinases, Proteolipids, Receptor Cross-Talk, Signal Transduction, Synovial Membrane, Toll-Like Receptor 4