Nature Immunology
6, 587 - 592 (2005)
Published online: 1 May 2005; | doi:10.1038/ni1200
ROS-dependent activation of the TRAF6-ASK1-p38 pathway is selectively required for TLR4-mediated innate immunityAtsushi Matsuzawa1, 2, 3, 7, Kaoru Saegusa1, 2, 3, 7, Takuya Noguchi1, 2, 3, 4, Chiharu Sadamitsu1, 2, 3, Hideki Nishitoh1, 2, 3, 4, Shigenori Nagai2, 5, Shigeo Koyasu2, 5, Kunihiro Matsumoto2, 6, Kohsuke Takeda1, 2, 3
& Hidenori Ichijo1, 2, 31
Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. 2
Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. 3
Strategic Approach to Drug Discovery and Development in Pharmaceutical Sciences, Center of Excellence Program, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. 4
Laboratory of Cell Signaling, Graduate School of Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8549, Japan. 5
Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. 6
Group of Signal Transduction, Department of Molecular Biology, Graduate School of Science, Nagoya University, Furou-chou, Chikusa-ku, Nagoya, Aichi 464-8602, Japan. 7
These authors contributed equally to this work.
Correspondence should be addressed to Hidenori Ichijo ichijo@mol.f.u-tokyo.ac.jpApoptosis signal−regulating kinase 1 (ASK1) is an evolutionarily conserved mitogen-activated protein 3-kinase that activates both Jnk and p38 mitogen-activated protein kinases. Here we used ASK1-deficient mice to show that ASK1 was selectively required for lipopolysaccharide-induced activation of p38 but not of Jnk or the transcription factor NF- B. ASK1 was required for the induction of proinflammatory cytokines dependent on Toll-like receptor 4 (TLR4) but not TLR2 or other TLRs. Consistent with this, ASK1-deficient mice were resistant to lipopolysaccharide-induced septic shock. Lipopolysaccharide induced the production of intracellular reactive oxygen species, which was required for the formation of a complex of the adaptor molecule TRAF6 and ASK1 and subsequent activation of the ASK1-p38 pathway. Our data demonstrate that the reactive oxygen species−dependent TRAF6-ASK1-p38 axis is crucial for TLR4-mediated mammalian innate immunity.
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