Gadd45α regulates p38-dependent dendritic cell cytokine production and Th1 differentiation
Gadd45α regulates p38-dependent dendritic cell cytokine production and Th1 differentiation
复制标题
DOI：
10.4049/jimmunol.178.7.4153
复制
发表时间：
2007-04-01
影响因子：
4.4
通讯作者：
Ashwell, Jonathan D.
中科院分区：
文献类型：
--
作者：
Jirmanova, Ludmila;Jankovic, Dragana;Ashwell, Jonathan D.
Gadd45 α通过涉及p38 Tyr磷酸化的T细胞替代途径抑制p38的激活（323）。考虑到T细胞p38可能在Th1发育中发挥作用，我们分析了Gadd45 α(-/-)小鼠对Th-skewing Ags的反应。尽管Gadd45 α (-/-) T细胞中p38活性呈组成性增加，但对弓形虫Ag （STAg）的Th1免疫反应减弱。与T细胞相比，树突状细胞（DC）缺乏替代的p38激活途径。Gadd45 α (-/-) dc对STAg的反应是低水平的MAP激酶级联依赖性p38激活、IL-12产生和CD40表达。转移到Gadd45 α(-/-)受体的野生型T细胞对STAg的Th1反应减弱，而转移到野生型宿主的Gadd45 α (-/-) T细胞表现正常。因此，Gadd45a对p38活性具有组织特异性和相反的功能，Gadd45 α调节dc中p38激活是体内Th1极化的关键事件。
Gadd45 alpha inhibits the activation of p38 by the T cell alternative pathway involving phosphorylation of p38 Tyr(323). Given that T cell p38 may play a role in Th1 development, the response to Th-skewing Ags was analyzed in Gadd45 alpha(-/-) mice. Despite constitutively increased p38 activity in Gadd45 alpha(-/-) T cells, the Th1 immune response to Toxoplasma gondii Ag (STAg), was' diminished. In contrast to T cells, dendritic cells (DC) lacked the alternative p38 activation pathway. Gadd45 alpha(-/-) DCs responded to STAg with low levels of MAP kinase cascade-dependent p38 activation, IL-12 production, and CD40 expression. Wild-type T cells transferred into Gadd45 alpha(-/-) recipients had a diminished Th1 response to STAg, whereas Gadd45 alpha(-/-) T cells transferred into wild-type hosts behaved normally. Therefore, Gadd45a has tissue-specific and opposing functions on p38 activity, and Gadd45 alpha-regulated p38 activation in DCs is a critical event in Th1 polarization in vivo.