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Prolonged Toll‐like receptor stimulation leads to down‐regulation of IRAK‐4 protein
Author(s) -
Hatao Fumihiko,
Muroi Masashi,
Hiki Naoki,
Ogawa Toshihisa,
Mimura Yoshikazu,
Kaminishi Michio,
Tanamoto Kenichi
Publication year - 2004
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.0504277
Subject(s) - biology , tlr4 , tlr2 , stimulation , toll like receptor , receptor , microbiology and biotechnology , kinase , tlr9 , phosphorylation , biochemistry , endocrinology , innate immune system , gene , gene expression , dna methylation
Interleukin‐1 receptor‐associated kinase (IRAK)‐4 is a key mediator in the Toll‐like receptor (TLR) signaling. We found that stimulation of TLR2, TLR4, or TLR9, but not TLR3, caused a decrease in IRAK‐4 protein without affecting its mRNA level in a mouse macrophage cell line, RAW 264. The decrease in IRAK‐4 was accompanied by the appearance of a smaller molecular weight protein (32 kD), which was recognized by an anti‐IRAK‐4 antibody raised against the C‐terminal region. The decrease in IRAK‐4 and the appearance of the 32‐kD protein occurred with slower kinetics than the activation of IRAK‐1 and were suppressed by inhibitors of the proteasome, inducible inhibitor of κBα phosphorylation or protein synthesis, but not by caspase inhibitors. These results indicate that prolonged stimulation of TLR2, TLR4, or TLR9 causes a down‐regulation of IRAK‐4 protein, which may be mediated through cleavage of IRAK‐4 by a protease induced by the activation of nuclear factor‐κB.