The p38 mitogen-activated protein kinase is required for IL-12-induced IFN-gamma expression

J Immunol. 2000 Aug 1;165(3):1374-80. doi: 10.4049/jimmunol.165.3.1374.

Abstract

IL-12 is a central immunoregulatory cytokine that promotes cell-mediated immune responses and the differentiation of naive CD4+ cells into Th1 cells. We and others have demonstrated that the Stat4 is critical for IFN-gamma production by activated T cells and Th1 cells. However, several studies have suggested that other pathways may be involved in IL-12-stimulated IFN-gamma expression. In this report we demonstrate that IL-12 activates mitogen-activated protein kinase kinase 3/6 (MKK) and p38 mitogen-activated protein kinase (MAPK), but not p44/42 (ERK) or stress-activated protein kinase/c-Jun N-terminal kinase MAPK. The activation of p38 MAPK is required for normal induction of IFN-gamma mRNA and IFN-gamma secretion by IL-12 in activated T cells and Th1 cells. Importantly, IL-12-stimulated p38 MAPK effector functions occur through a Stat4-independent mechanism and correlate with increased serine phosphorylation of activating transcription factor-2. The requirement for p38 MAPK in IL-12 function suggests that this pathway may be an important in vivo target for the anti-inflammatory actions of p38 MAPK inhibitors.

Publication types

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

MeSH terms

  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / physiology
  • Enzyme Activation / drug effects
  • Enzyme Activation / immunology
  • Enzyme Inhibitors / pharmacology
  • Imidazoles / pharmacology
  • Interferon-gamma / biosynthesis*
  • Interleukin-12 / physiology*
  • Lymphocyte Activation
  • MAP Kinase Kinase 3
  • MAP Kinase Kinase 6
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 10
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / metabolism
  • Mitogen-Activated Protein Kinases / physiology*
  • Protein-Tyrosine Kinases / metabolism
  • Pyridines / pharmacology
  • STAT4 Transcription Factor
  • Signal Transduction / drug effects
  • Signal Transduction / immunology
  • T-Lymphocytes / enzymology
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • Trans-Activators / deficiency
  • Trans-Activators / genetics
  • Trans-Activators / physiology
  • p38 Mitogen-Activated Protein Kinases

Substances

  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Imidazoles
  • Pyridines
  • STAT4 Transcription Factor
  • Stat4 protein, mouse
  • Trans-Activators
  • Interleukin-12
  • Interferon-gamma
  • Mitogen-Activated Protein Kinase 10
  • Protein-Tyrosine Kinases
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 3
  • MAP Kinase Kinase 6
  • Map2k3 protein, mouse
  • Map2k6 protein, mouse
  • Mitogen-Activated Protein Kinase Kinases
  • SB 203580
  • 4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole