GADD45beta/GADD45gamma and MEKK4 comprise a genetic pathway mediating STAT4-independent IFNgamma production in T cells.
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.
Chi
Hongbo
H
Section of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.
Lu
Binfeng
B
Takekawa
Mutsuhiro
M
Davis
Roger J
RJ
Flavell
Richard A
RA
D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D048768:MAP Kinase Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050797:STAT4 Transcription Factor; D018417:Th1 Cells / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000097642:GADD45 Proteins
D000943:Antigens, Differentiation; D004268:DNA-Binding Proteins; D007371:Interferon-gamma; D047908:Intracellular Signaling Peptides and Proteins; D048768:MAP Kinase Kinase Kinase 4; D050797:STAT4 Transcription Factor; D015534:Trans-Activators; D048051:p38 Mitogen-Activated Protein Kinases; D000097642:GADD45 Proteins; C490125:Gadd45b protein, mouse; C494090:STAT4 protein, human; C494091:Stat4 protein, mouse; C482780:Map3k4 protein, mouse