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Published online before print July 16, 2004

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(Journal of Leukocyte Biology. 2004;76:904-908.)
© 2004 by Society for Leukocyte Biology

Prolonged Toll-like receptor stimulation leads to down-regulation of IRAK-4 protein

Fumihiko Hatao^*,, Masashi Muroi^*, Naoki Hiki, Toshihisa Ogawa, Yoshikazu Mimura, Michio Kaminishi and Ken-ichi Tanamoto^*,1

^* Division of Microbiology, National Institute of Health Sciences, Tokyo, Japan; and
Department of Metabolic Care and Gastrointestinal Surgery, Graduate School of Medicine, and
Surgical Center, The University of Tokyo, Japan

¹ Correspondence: Division of Microbiology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya, Tokyo 158-8501, Japan. E-mail: tanamoto{at}nihs.go.jp

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 B 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-B.

Key Words: monocytes/macrophages • bacterial lipoprotein • CpG-DNA • lipopolysaccharide • protein kinases

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