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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.

Type

Journal article

Journal

J Immunol

Publication Date

01/03/2008

Volume

180

Pages

3485 - 3491

Keywords

Antigens, CD29, Bacterial Proteins, Cell Communication, Fibroblasts, Focal Adhesion Kinase 1, Humans, Integrin alpha5, 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