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IRAK‐M selectively modulates the alternative, instead of the classical NFkB pathway in a ligand‐specific fashion
Author(s) -
Li Liwu,
Su jianmin,
Surace Michael
Publication year - 2008
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.22.1_supplement.672.1
Subject(s) - relb , kinase , iκb kinase , phosphorylation , signal transduction , ligand (biochemistry) , nf κb , chemistry , microbiology and biotechnology , tlr4 , nfkb1 , iκbα , p50 , biology , receptor , biochemistry , gene , transcription factor
Innate immunity signaling process is controlled by numerous positive as well as negative mediators. The interleukin‐1 receptor associated kinase M (IRAK‐M) is one of the negative regulators that contribute to attenuation of NF‐kappa‐B activation. However, the molecular mechanism involved is poorly defined. We observed that IRAK‐M selectively suppressed the NIK‐IKKalpha‐mediated alternative NF‐kappa‐B pathway. Deletion of IRAK‐M led to NIK stabilization, favored the formation of IKK‐alpha/IKK‐alpha homo‐dimer instead of IKK‐alpha/IKK‐beta heter‐dimer, and enhanced RelB nuclear distribution. In contrast, the p65 nuclear localization and phosphorylation was not affected by IRAK‐M deficiency. We found that IRAK‐M deletion led to accelerated synthesis of I‐kappa‐B‐alpha, as well as increased expression of selected cytokines such as IL‐6. Furthermore, the elevated IL‐6 expression can be ablated when RelB was knocked down with specific siRNA. We also demonstrated that the observed inhibitory effect of IRAK‐M was primarily limited to TLR‐2 ligand, instead of TLR4. Taken together, our findings suggest that IRAK‐M negatively regulates alternative NF‐kappa‐B pathway in a ligand specific manner.