Crosstalk between PKCzeta and the IL4/Stat6 pathway during T-cell-mediated hepatitis

EMBO J. 2004 Nov 24;23(23):4595-605. doi: 10.1038/sj.emboj.7600468. Epub 2004 Nov 4.

Abstract

PKCzeta is required for nuclear factor kappa-B (NF-kappaB) activation in several cell systems. NF-kappaB is a suppressor of liver apoptosis during development and in concanavalin A (ConA)-induced T-cell-mediated hepatitis. Here we show that PKCzeta-/- mice display inhibited ConA-induced NF-kappaB activation and reduced damage in liver. As the IL-4/Stat6 pathway is necessary for ConA-induced hepatitis, we addressed here the potential role of PKCzeta in this cascade. Interestingly, the loss of PKCzeta severely attenuated serum IL-5 and liver eotaxin-1 levels, two critical mediators of liver damage. Stat6 tyrosine phosphorylation and Jak1 activation were ablated in the liver of ConA-injected PKCzeta-/- mice and in IL-4-stimulated PKCzeta-/- fibroblasts. PKCzeta interacts with and phosphorylates Jak1 and PKCzeta activity is required for Jak1 function. In contrast, Par-4-/- mice have increased sensitivity to ConA-induced liver damage and IL-4 signaling. This unveils a novel and critical involvement of PKCzeta in the IL-4/Stat6 signaling pathway in vitro and in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Chemical and Drug Induced Liver Injury / etiology
  • Chemical and Drug Induced Liver Injury / immunology
  • Chemical and Drug Induced Liver Injury / metabolism*
  • Chemokine CCL11
  • Chemokines, CC / metabolism
  • Concanavalin A
  • Enzyme Activation
  • Fibroblasts / metabolism
  • Interleukin-4 / physiology*
  • Interleukin-5 / blood
  • Janus Kinase 1
  • Liver / drug effects
  • Liver / metabolism*
  • Liver / pathology
  • Mice
  • Mice, Knockout
  • NF-kappa B / metabolism
  • Phosphorylation
  • Protein Kinase C / genetics
  • Protein Kinase C / physiology*
  • Protein-Tyrosine Kinases / metabolism
  • Receptors, Thrombin / genetics
  • Receptors, Thrombin / metabolism
  • STAT6 Transcription Factor
  • Signal Transduction / physiology
  • T-Lymphocytes / immunology*
  • Trans-Activators / physiology*

Substances

  • Ccl11 protein, mouse
  • Chemokine CCL11
  • Chemokines, CC
  • Interleukin-5
  • NF-kappa B
  • Receptors, Thrombin
  • STAT6 Transcription Factor
  • Stat6 protein, mouse
  • Trans-Activators
  • Concanavalin A
  • Interleukin-4
  • Protein-Tyrosine Kinases
  • Jak1 protein, mouse
  • Janus Kinase 1
  • protein kinase C zeta
  • Protein Kinase C
  • protease-activated receptor 4