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Inducible nitric acid synthase/Src axis mediates TLR3 Tyr759 phosphorylation, nuclear translocation of IRF3 and IRF7 that leads to interferon‐beta synthesis in double‐stranded RNA‐stimulated macrophage
Author(s) -
Maa Ming-Chei,
Chang Miao Ying,
Leu Tzeng-Horng
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.lb156
Subject(s) - irf3 , lyn , tlr3 , irf7 , proto oncogene tyrosine protein kinase src , nitric oxide synthase , interferon , microbiology and biotechnology , phosphorylation , chemistry , biology , cancer research , toll like receptor , receptor , nitric oxide , biochemistry , immunology , innate immune system , endocrinology
As a frequent byproduct of viral infection, double‐stranded RNA is recognized by Toll‐like receptor 3 (TLR3) and triggers signaling pathways that result in production of interferon‐β (IFN‐β). Despite mounting evidence reveals the involvement of protein tyrosine kinases (PTKs) in this process, the identity of the responsive PTKs is still elusive. In this study, we demonstrated Src attenuation impaired TLR3 Pi‐Tyr759, nuclear accumulation of transcription factors IRF3 and IRF7, and the increment of ifn‐ β transcript and IFN‐β production in polyinosinic‐polycytidylic acid (polyI:C)‐stimulated macrophages. Remarkably, re‐introduction of siRNA‐resistant avian Src reversed all these defects. Consistent with the expression of Src was inducible‐nitric oxide synthase (iNOS)‐dependent, polyI:C‐elicited TLR3 Pi‐Tyr759, nuclear translocation of IRF3 and IRF7, as well as IFN‐β generation were inhibited in iNOS‐null macrophages, which could be rescued by SNAP (a NO donor). Notably, Lyn and FAK did not contribute to polyI:C‐evoked IFN‐β secretion. This was the first time an essential role of iNOS/Src axis in IFN‐β production in TLR3‐engaged macrophages was corroborated. This work was supported by the National Science Council (NSC98‐2311‐B‐039‐002‐MY3).