GADD45beta/GADD45gamma and MEKK4 comprise a genetic pathway mediating STAT4-independent IFNgamma production in T cells

EMBO J. 2004 Apr 7;23(7):1576-86. doi: 10.1038/sj.emboj.7600173. Epub 2004 Mar 25.

Abstract

The stress-inducible molecules GADD45beta and GADD45gamma have been implicated in regulating IFNgamma production in CD4 T cells. However, how GADD45 proteins function has been controversial. MEKK4 is a MAP kinase kinase kinase that interacts with GADD45 in vitro. Here we generated MEKK4-deficient mice to define the function and regulation of this pathway. CD4 T cells from MEKK4-/- mice have reduced p38 activity and defective IFNgamma synthesis. Expression of GADD45beta or GADD45gamma promotes IFNgamma production in MEKK4+/+ T cells, but not in MEKK4-/- cells or in cells treated with a p38 inhibitor. Thus, MEKK4 mediates the action of GADD45beta and GADD45gamma on p38 activation and IFNgamma production. During Th1 differentiation, the GADD45beta/GADD45gamma/MEKK4 pathway appears to integrate upstream signals transduced by both T cell receptor and IL12/STAT4, leading to augmented IFNgamma production in a process independent of STAT4.

Publication types

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

MeSH terms

  • Animals
  • Antigens, Differentiation / genetics
  • Antigens, Differentiation / metabolism*
  • Cell Differentiation
  • DNA-Binding Proteins / metabolism*
  • Enzyme Activation
  • GADD45 Proteins
  • Gene Expression Regulation
  • Humans
  • Interferon-gamma / metabolism*
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • MAP Kinase Kinase Kinase 4 / genetics
  • MAP Kinase Kinase Kinase 4 / metabolism*
  • MAP Kinase Signaling System / physiology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • STAT4 Transcription Factor
  • Th1 Cells / physiology*
  • Trans-Activators / metabolism*
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Antigens, Differentiation
  • DNA-Binding Proteins
  • Gadd45b protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • STAT4 Transcription Factor
  • STAT4 protein, human
  • Stat4 protein, mouse
  • Trans-Activators
  • Interferon-gamma
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 4
  • Map3k4 protein, mouse