Chi Hongbo, Lu Binfeng, Takekawa Mutsuhiro, Davis Roger J, Flavell Richard A
Section of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.
EMBO J. 2004 Apr 7;23(7):1576-86. doi: 10.1038/sj.emboj.7600173. Epub 2004 Mar 25.
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.
应激诱导分子GADD45β和GADD45γ与调节CD4 T细胞中γ干扰素（IFNγ）的产生有关。然而，GADD45蛋白的功能一直存在争议。MEKK4是一种丝裂原活化蛋白激酶激酶激酶，在体外与GADD45相互作用。在此，我们培育出MEKK4缺陷小鼠，以确定该信号通路的功能和调控机制。来自MEKK4基因敲除小鼠的CD4 T细胞，其p38活性降低，γ干扰素合成存在缺陷。GADD45β或GADD45γ的表达可促进MEKK4基因野生型T细胞中γ干扰素的产生，但在MEKK4基因敲除细胞或用p38抑制剂处理的细胞中则不然。因此，MEKK4介导GADD对p38的激活作用及γ干扰素的产生。在Th1分化过程中，GADD45β/GADD45γ/MEKK4信号通路似乎整合了由T细胞受体和IL12/STAT4转导的上游信号，从而在一个独立于STAT4的过程中增强γ干扰素的产生。
