Selective requirement of p38α MAPK in cytokine-dependent, but not antigen receptor-dependent, Th1 responses
Selective requirement of p38α MAPK in cytokine-dependent, but not antigen receptor-dependent, Th1 responses
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DOI：
10.4049/jimmunol.176.8.4616
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发表时间：
2006-04-15
影响因子：
4.4
通讯作者：
Murphy, Kenneth M.
中科院分区：
文献类型：
--
作者：
Berenson, Lisa S.;Yang, Jianfei;Murphy, Kenneth M.
p38 MAPK通路在Th 1发育中的作用一直存在争议，因为上游p38激活剂或p38活性修饰剂的间接操纵对CD 4（+）T细胞中IFN-γ的产生具有不同的影响。关于药理学抑制或p38显性阴性突变体的特异性的不确定性降低了关于p38 α亚型在Th 1发育中的作用的结论的强度。此外，一些上游p38激活剂，如MAPK激酶3，对Th 1发展的影响不如其他操作，如显性负性p38突变体的表达的影响强。最后，胚胎致死性阻止了对p38 α缺陷T细胞的直接检查。为了测试在Th 1分化中对p38 a的需求，我们使用RAG 2（-/-）胚泡互补和DO11.10 TCR的逆转录病毒表达产生Ag特异性p38 a（+/-）和p38 α（-/-）CD 4（+）T细胞。在Th 1条件下培养的p38 α（-/-）T细胞中，响应TCR信号传导的IFN-γ产生是正常的，这意味着正常的Th 1发育。然而，与TCR诱导的IFN-γ分泌相比，p38 α（-/-）Th 1细胞在IL-12/IL-18刺激的IFN-γ分泌中具有更大的缺陷。这些结果表明，Th 1细胞中p38 α的活性相对限于在两种替代途径之一中起作用（即，细胞因子诱导的），其可以诱导分化的Th 1细胞中IFN-γ的产生，但是p38 α对于Th 1定型和发育本身的过程不是必需的。
The role of the p38 MAPK pathway in Th1 development has been controversial, because indirect manipulations of either upstream p38 activators or modifiers of p38 activity have had variable effects on IFN-gamma production in CD4(+) T cells. Uncertainties regarding the specificity of pharmacologic inhibition or p38 dominant negative mutants diminish the strength of conclusions about the role of the p38 alpha isoform in Th1 development. Also, the effects of some upstream p38 activators, such as MAPK kinase 3, on Th1 development are not as strong as the effects of other manipulations, such as the expression of a dominant negative p38 mutant. Finally, embryonic lethality has prevented a direct examination of p38 alpha-deficient T cells. To test the requirement for p38a in Th1 differentiation, we generated Ag-specific p38a(+/-) and p38 alpha(-/-) CD4(+) T cells using RAG2(-/-) blastocyst complementation and retroviral expression of the DO11.10 TCR. IFN-gamma production in response to TCR signaling is normal in p38 alpha(-/-) T cells cultured in Th1 conditions, implying normal Thl development. However, p38 alpha(-/-) Th1 cells have a much greater defect in IFN-gamma secretion stimulated by IL-12/IL-18 compared with TCR-induced IFN-gamma secretion. These results suggest that the activity of p38 alpha in Th1 cells is relatively restricted to acting in one of two alternative pathways (i.e., cytokine induced) that can induce the production of IFN-gamma in differentiated Th1 cells, but that p38 alpha is not required for the process of Th1 commitment and development itself.