Essential function for the kinase TAK1 in innate and adaptive immune responses.
Transforming growth factor-beta-activated kinase 1 (TAK1) has been linked to interleukin 1 receptor and tumor necrosis factor receptor signaling. Here we generated mouse strains with conditional expression of a Map3k7 allele encoding part of TAK1. TAK1-deficient embryonic fibroblasts demonstrated loss of responses to interleukin 1beta and tumor necrosis factor. Studies of mice with B cell-specific TAK1 deficiency showed that TAK1 was indispensable for cellular responses to Toll-like receptor ligands, CD40 and B cell receptor crosslinking. In addition, antigen-induced immune responses were considerably impaired in mice with B cell-specific TAK1 deficiency. TAK1-deficient cells failed to activate transcription factor NF-kappaB and mitogen-activated protein kinases in response to interleukin 1beta, tumor necrosis factor and Toll-like receptor ligands. However, TAK1-deficient B cells were able to activate NF-kappaB but not the kinase Jnk in response to B cell receptor stimulation. These results collectively indicate that TAK1 is key in the cellular response to a variety of stimuli.
Sato
Shintaro
S
Akira Innate Immunity Project, Exploratory Research for Advanced Technology, Japan Science and Technology Agency.
Sanjo
Hideki
H
Takeda
Kiyoshi
K
Ninomiya-Tsuji
Jun
J
Yamamoto
Masahiro
M
Kawai
Taro
T
Matsumoto
Kunihiro
K
Takeuchi
Osamu
O
Akira
Shizuo
S
D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology*; D019013:CD40 Antigens / Q000494:pharmacology; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D017353:Gene Deletion; D007113:Immunity, Innate; D020381:Interleukin-17 / Q000494:pharmacology; D038041:Lymphopoiesis; D020930:MAP Kinase Kinase Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000276:immunology; D051379:Mice; D008817:Mice, Mutant Strains; D016328:NF-kappa B / Q000494:pharmacology; D011947:Receptors, Antigen, B-Cell / Q000819:agonists / Q000276:immunology; D011956:Receptors, Cell Surface / Q000276:immunology; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000099151:MAP Kinase Kinase Kinase 7
D019013:CD40 Antigens; D020381:Interleukin-17; D020930:MAP Kinase Kinase Kinases; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D011947:Receptors, Antigen, B-Cell; D011956:Receptors, Cell Surface; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D000099151:MAP Kinase Kinase Kinase 7