Abstract
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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Agammaglobulinaemia Tyrosine Kinase
-
Bacterial Proteins / physiology
-
Cell Communication / immunology*
-
Fibroblasts / enzymology
-
Fibroblasts / pathology
-
Focal Adhesion Kinase 1 / metabolism
-
Focal Adhesion Kinase 1 / physiology*
-
Humans
-
Integrin alpha5 / metabolism
-
Integrin alpha5 / physiology
-
Integrin beta1 / metabolism
-
Integrin beta1 / physiology
-
Lymphocyte Activation / immunology
-
Membrane Transport Proteins / metabolism
-
Membrane Transport Proteins / physiology*
-
Multigene Family / immunology
-
Myelin Proteins / metabolism
-
Myelin Proteins / physiology*
-
Myelin and Lymphocyte-Associated Proteolipid Proteins
-
Myeloid Differentiation Factor 88 / metabolism
-
Myeloid Differentiation Factor 88 / physiology*
-
Protein-Tyrosine Kinases / metabolism
-
Protein-Tyrosine Kinases / physiology*
-
Proteolipids / metabolism
-
Proteolipids / physiology*
-
Receptor Cross-Talk / immunology
-
Signal Transduction / immunology*
-
Synovial Membrane / enzymology
-
Synovial Membrane / pathology
-
Toll-Like Receptor 4 / metabolism
-
Toll-Like Receptor 4 / physiology
Substances
-
Bacterial Proteins
-
Integrin alpha5
-
Integrin beta1
-
MAL protein, human
-
MYD88 protein, human
-
Membrane Transport Proteins
-
Myelin Proteins
-
Myelin and Lymphocyte-Associated Proteolipid Proteins
-
Myeloid Differentiation Factor 88
-
Proteolipids
-
TLR4 protein, human
-
Toll-Like Receptor 4
-
protein I-II, Streptococcus mutans
-
BMX protein, human
-
Protein-Tyrosine Kinases
-
Agammaglobulinaemia Tyrosine Kinase
-
BTK protein, human
-
Focal Adhesion Kinase 1
-
PTK2 protein, human