IKKbeta is required for prevention of apoptosis mediated by cell-bound but not by circulating TNFalpha

Immunity. 2003 Nov;19(5):725-37. doi: 10.1016/s1074-7613(03)00301-7.

Abstract

IkappaB kinase beta (IKKbeta) is required for NF-kappaB activation and suppression of TNFalpha-mediated liver apoptosis. To investigate how IKKbeta suppresses apoptosis, we generated hepatocyte-specific Ikkbeta knockout mice, Ikkbeta(Deltahep), which exhibit little residual NF- kappaB activity but are healthy with normal liver function. Unexpectedly, Ikkbeta(Deltahep) mice are slightly more sensitive than controls to LPS-induced liver apoptosis but are highly susceptible to liver destruction following concanavalin A (ConA)-induced T cell activation. Unlike LPS, a potent inducer of circulating TNFalpha, ConA exerts cytotoxic effects through cell-bound TNFalpha, which activates type 1 and 2 TNF receptors (TNFR). While TNFR2 does not contribute to NF-kappaB activation, it is important for ConA-induced JNK activation, which is augmented by the absence of IKKbeta. Using JNK-deficient mice we show that JNK is required for ConA-induced liver damage. Thus, the antiapoptotic function of IKKbeta, which is most critical in situations that involve cell-bound TNFalpha, is mediated partially through attenuation of JNK activity.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antigens, CD / metabolism
  • Apoptosis / physiology*
  • Concanavalin A / metabolism
  • I-kappa B Kinase
  • JNK Mitogen-Activated Protein Kinases
  • Lipopolysaccharides / metabolism
  • Liver / pathology
  • Liver / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitogen-Activated Protein Kinases / metabolism
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Receptors, Tumor Necrosis Factor / metabolism
  • Receptors, Tumor Necrosis Factor, Type II
  • T-Lymphocytes / physiology
  • Tumor Necrosis Factor-alpha / metabolism*

Substances

  • Antigens, CD
  • Lipopolysaccharides
  • Receptors, Tumor Necrosis Factor
  • Receptors, Tumor Necrosis Factor, Type II
  • Tumor Necrosis Factor-alpha
  • Concanavalin A
  • Protein-Serine-Threonine Kinases
  • Chuk protein, mouse
  • I-kappa B Kinase
  • Ikbkb protein, mouse
  • Ikbke protein, mouse
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases