IL-18-stimulated GADD45 beta required in cytokine-induced, but not TCR-induced, IFN-gamma production

Nat Immunol. 2001 Feb;2(2):157-64. doi: 10.1038/84264.

Abstract

Interleukin-12 (IL-12) and IL-18 induce synergistic transcription of interferon gamma (IFN-gamma) that is T cell receptor (TCR)-independent, not inhibited by cyclosporin A and requires new protein synthesis. To characterize this pathway, we screened for genes that are induced in IL-12- and IL-18-treated T helper type 1 cells. GADD45 beta, which activates mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase kinase 4 (MEKK4), was induced by IL-18 and augmented by IL-12. GADD45 beta expression in naïve CD4+ T cells activated p38 MAPK and selectively increased cytokine-induced, but not TCR-induced, IFN-gamma production. Kinase-inactive MEKK4 and inhibition of the p38 MAPK pathway both selectively inhibit cytokine-induced, but not TCR-induced, IFN-gamma production. Thus, the synergy between IL-12 and IL-18 may involve GADD45 beta induction, which can maintain the MEKK4 and p38 MAPK activation that is necessary for cytokine-induced, but not TCR-induced, IFN-gamma production.

Publication types

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

MeSH terms

  • Animals
  • Base Sequence
  • Cell Line
  • Cytokines / pharmacology
  • DNA Primers / genetics
  • Humans
  • Interferon-gamma / biosynthesis*
  • Interleukin-12 / pharmacology
  • Interleukin-18 / pharmacology*
  • Intracellular Signaling Peptides and Proteins
  • MAP Kinase Kinase Kinase 4
  • MAP Kinase Kinase Kinases / genetics
  • MAP Kinase Kinase Kinases / metabolism
  • Mice
  • Mice, Transgenic
  • Mitogen-Activated Protein Kinases / metabolism
  • Protein Biosynthesis
  • Proteins / genetics
  • Proteins / metabolism*
  • Receptors, Antigen, T-Cell / metabolism
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • p38 Mitogen-Activated Protein Kinases

Substances

  • Cytokines
  • DNA Primers
  • GADD45 protein
  • Interleukin-18
  • Intracellular Signaling Peptides and Proteins
  • Proteins
  • Receptors, Antigen, T-Cell
  • Interleukin-12
  • Interferon-gamma
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 4
  • MAP Kinase Kinase Kinases
  • MAP3K4 protein, human
  • Map3k4 protein, mouse