期刊
EMBO JOURNAL
卷 23, 期 7, 页码 1576-1586出版社
WILEY
DOI: 10.1038/sj.emboj.7600173
关键词
GADD45; interferon; p38; STAT4; T cell differentiation
资金
- NIAID NIH HHS [1 P01 AI36529, P01 AI036529] Funding Source: Medline
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 GADD4Sbeta and GADD45gamma on p38 activation and lFNgamma 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.
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