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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

Journal of immunology (Baltimore, Md. : 1950)

Publication Date

03/2008

Volume

180

Pages

3485 - 3491

Addresses

Laboratoire Physiopathologie des Arthrites, Université Louis Pasteur de Strasbourg, Unité de Formation et de Recherche Sciences Pharmaceutiques, Illkirch, France.

Keywords

Synovial Membrane, Fibroblasts, Humans, Proteolipids, Bacterial Proteins, Membrane Transport Proteins, Myelin Proteins, Integrin alpha5, Antigens, CD29, Lymphocyte Activation, Cell Communication, Signal Transduction, Receptor Cross-Talk, Multigene Family, Toll-Like Receptor 4, Focal Adhesion Kinase 1, Protein-Tyrosine Kinases, Myeloid Differentiation Factor 88, Myelin and Lymphocyte-Associated Proteolipid Proteins