Regulation of innate and adaptive immune responses by MAP kinase phosphatase 5
Regulation of innate and adaptive immune responses by MAP kinase phosphatase 5
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DOI：
10.1038/nature02764
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发表时间：
2004-08-12
期刊：
影响因子：
64.8
通讯作者：
Dong, C
中科院分区：
文献类型：
--
作者：
Zhang, YL;Blattman, JN;Dong, C
丝裂原活化蛋白(MAP)激酶是免疫反应中必不可少的调节因子(1)，它们的活性受激酶和磷酸酶的调节。MKP是一个功能进化保守的双特异性磷酸酶家族(2，3)。到目前为止，已经鉴定了许多哺乳动物MKPs(2，3)，但它们在MAP激酶负调控中的具体生理功能尚未从基因上确定。在这里，我们研究了在没有MKP5的情况下的先天和获得性免疫反应。在Mkp5(也称为Dusp10)缺陷的小鼠细胞中，JNK活性选择性地增强。在先天免疫反应中，Mkp5缺陷细胞产生的致炎细胞因子水平大大增加，并且比野生型细胞表现出更大的T细胞激活。然而，Mkp5缺陷的T细胞在激活时增殖不良，导致对实验性自身免疫性脑脊髓炎的抵抗力增强。相比之下，与野生型细胞相比，Mkp5缺陷的CD4(+)和CD8(+)效应T细胞产生的细胞因子水平显著增加，这导致了对淋巴细胞性脉络膜脑膜炎病毒二次感染的更强大和更迅速的致命免疫反应。因此，MKP5在先天免疫反应和获得性免疫反应中都具有重要作用，是免疫疾病治疗干预的新靶点。
Mitogen-activated protein ( MAP) kinases are essential regulators in immune responses(1), and their activities are modulated by kinases and phosphatases. MAP kinase phosphatase (MKP) is a family of dual-specificity phosphatases whose function is evolutionarily conserved(2,3). A number of mammalian MKPs have been identified so far(2,3), but their specific physiological functions in negative regulation of MAP kinases have not been genetically defined. Here we examine innate and adaptive immune responses in the absence of MKP5. JNK activity was selectively increased in Mkp5 ( also known as Dusp10)-deficient mouse cells. Mkp5-deficient cells produced greatly enhanced levels of pro-inflammatory cytokines during innate immune responses and exhibited greater T-cell activation than their wild-type counterparts. However, Mkp5-deficient T cells proliferated poorly upon activation, which resulted in increased resistance to experimental autoimmune encephalomyelitis. By contrast, Mkp5-deficient CD4(+) and CD8(+) effector T cells produced significantly increased levels of cytokines compared with wild-type cells, which led to much more robust and rapidly fatal immune responses to secondary infection with lymphocytic choriomeningitis virus. Therefore, MKP5 has a principal function in both innate and adaptive immune responses, and represents a novel target for therapeutic intervention of immune diseases.