MAP激酶磷酸酶（MKPs）是在包括免疫响应在内的哺乳动物系统内一系列生理过程的调节中所涉及的信号蛋白，然而它们在活体中所发挥的特定作用尚未在遗传上予以确定。用缺失MKP5的小鼠所做的一项研究表明，MKP5基因在免疫响应中被表达和调节，它降低两种MAP激酶磷酸酶JNK 和 AP-1的活性，缺失MKP5的小鼠表现出增强的先天和后天免疫响应。由于MKP5在两种类型的免疫响应中都扮演一个角色，所以它是免疫疾病治疗性干预中的一个首要目标。
Regulation of innate and adaptive immune responses by MAP kinase phosphatase 5
YONGLIANG ZHANG1,†, JOSEPH N. BLATTMAN1, NORMAN J. KENNEDY2, JULIE DUONG1, THANG NGUYEN1, YING WANG1, ROGER J. DAVIS2, PHILIP D. GREENBERG1, RICHARD A. FLAVELL3,* & CHEN DONG1,*,†
1 Department of Immunology, University of Washington, Seattle, Washington 98195-7650, USA
2 Howard Hughes Medical Institute, University of Massachusetts, Worcester, Massachusetts 01605, USA
3 Section of Immunobiology, Howard Hughes Medical Institute, Yale University, New Haven, Connecticut 06520, USA
* These authors contributed equally to this work
† Present address: Department of Immunology, University of Texas, MD Anderson Cancer Center, Houston, Texas 77030, USA
Correspondence and requests for materials should be addressed to R.A.F (richard.flavell@yale.edu) or C.D. (cdong@mdanderson.org).
Mitogen-activated protein (MAP) kinases are essential regulators in immune responses, 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. A number of mammalian MKPs have been identified so far, 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.
