ROS-dependent activation of the TRAF6-ASK1-p38 pathway is selectively required for TLR4-mediated innate immunity.
Apoptosis 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-kappaB. 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.
Matsuzawa
Atsushi
A
Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Saegusa
Kaoru
K
Noguchi
Takuya
T
Sadamitsu
Chiharu
C
Nishitoh
Hideki
H
Nagai
Shigenori
S
Koyasu
Shigeo
S
Matsumoto
Kunihiro
K
Takeda
Kohsuke
K
Ichijo
Hidenori
H
D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D007113:Immunity, Innate; D066298:In Vitro Techniques; D008070:Lipopolysaccharides / Q000633:toxicity; D048848:MAP Kinase Kinase Kinase 5 / Q000172:deficiency* / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017382:Reactive Oxygen Species / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000378:metabolism*; D012772:Shock, Septic / Q000276:immunology; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism*; D051197:Toll-Like Receptor 4; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D016207:Cytokines; D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species; D011971:Receptors, Immunologic; D048029:TNF Receptor-Associated Factor 6; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; C482859:Map3k5 protein, mouse