Essential Function for the Kinase TAK1 in Innate and Adaptive Immune Responses

Nat Immunol. 2005 Nov;6(11):1087-95. doi: 10.1038/ni1255. Epub 2005 Sep 25.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / drug effects
  • B-Lymphocytes / enzymology*
  • B-Lymphocytes / immunology*
  • CD40 Antigens / pharmacology
  • Embryo, Mammalian / cytology
  • Fibroblasts / drug effects
  • Fibroblasts / enzymology
  • Gene Deletion
  • Immunity, Innate*
  • Interleukin-17 / pharmacology
  • Lymphopoiesis
  • MAP Kinase Kinase Kinases / deficiency
  • MAP Kinase Kinase Kinases / genetics
  • MAP Kinase Kinase Kinases / physiology*
  • Membrane Glycoproteins / immunology
  • Mice
  • Mice, Mutant Strains
  • NF-kappa B / pharmacology
  • Receptors, Antigen, B-Cell / agonists
  • Receptors, Antigen, B-Cell / immunology
  • Receptors, Cell Surface / immunology
  • Toll-Like Receptors
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • CD40 Antigens
  • Interleukin-17
  • Membrane Glycoproteins
  • NF-kappa B
  • Receptors, Antigen, B-Cell
  • Receptors, Cell Surface
  • Toll-Like Receptors
  • Tumor Necrosis Factor-alpha
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7