ROS-dependent activation of the TRAF6-ASK1-p38 pathway is selectively required for TLR4-mediated innate immunity

Atsushi Matsuzawa, Kaoru Saegusa, Takuya Noguchi, Chiharu Sadamitsu, Hideki Nishitoh, Shigenori Nagai, Shigeo Koyasu, Kunihiro Matsumoto, Kohsuke Takeda, Hidenori Ichijo

Research output: Contribution to journalArticle

498 Citations (Scopus)

Abstract

Apoptosis signal-regulating kinase 1 (ASK1) is an evolutionary 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-κB. 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.

Original languageEnglish
Pages (from-to)587-592
Number of pages6
JournalNature Immunology
Volume6
Issue number6
DOIs
Publication statusPublished - 2005 Dec 8
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Matsuzawa, A., Saegusa, K., Noguchi, T., Sadamitsu, C., Nishitoh, H., Nagai, S., Koyasu, S., Matsumoto, K., Takeda, K., & Ichijo, H. (2005). ROS-dependent activation of the TRAF6-ASK1-p38 pathway is selectively required for TLR4-mediated innate immunity. Nature Immunology, 6(6), 587-592. https://doi.org/10.1038/ni1200