Article

  • The EMBO Journal (2004) 23, 1576 - 1586
  • doi:10.1038/sj.emboj.7600173

Published online: 25 March 2004

GADD45bold beta/GADD45big gamma and MEKK4 comprise a genetic pathway mediating STAT4-independent IFNbig gamma production in T cells

Hongbo Chi1, Binfeng Lu1, Mutsuhiro Takekawa2,3, Roger J Davis4 and Richard A Flavell1,5

  1. Section of Immunobiology, Yale University School of Medicine, New Haven, CT, USA
  2. Division of Molecular Cell Signaling, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
  3. PRESTO, Japan Science and Technology Corporation (JST), Saitama, Japan
  4. Howard Hughes Medical Institute and Program in Molecular Medicine, Department of Biochemistry & Molecular Biology, University of Massachusetts Medical School, Worcester, MA, USA
  5. Howard Hughes Medical Institute, New Haven, CT, USA

Correspondence to:

Richard A Flavell, Section of Immunobiology, HHMI, Yale University School of Medicine, 300 Cedar Street, TAC S-569, New Haven, CT 06520-8011, USA. Tel.: +1 203 737 2216; Fax: +1 203 737 2958; E-mail: richard.flavell@yale.edu

Received 18 November 2003; Accepted 23 February 2004


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.

  • Keywords:

    • GADD45,
    • interferon,
    • p38,
    • STAT4,
    • T cell differentiation
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