Regulation of innate and adaptive immune responses by MAP kinase phosphatase 5

Yongliang Zhang, Joseph N. Blattman, Norman J. Kennedy, Julie Duong, Thang Nguyen, Ying Wang, Roger J. Davis, Philip D. Greenberg, Richard A. Flavell () and Chen Dong ()
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Yongliang Zhang: University of Washington
Joseph N. Blattman: University of Washington
Norman J. Kennedy: University of Massachusetts
Julie Duong: University of Washington
Thang Nguyen: University of Washington
Ying Wang: University of Washington
Roger J. Davis: University of Massachusetts
Philip D. Greenberg: University of Washington
Richard A. Flavell: Yale University
Chen Dong: University of Washington

Nature, 2004, vol. 430, issue 7001, 793-797

Abstract: Abstract Mitogen-activated protein (MAP) kinases are essential regulators in immune responses1, and their activities are modulated by kinases and phosphatases. MAP kinase phosphatase (MKP) is a family of dual-specificity phosphatases whose function is evolutionarily conserved2,3. A number of mammalian MKPs have been identified so far2,3, 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.

Date: 2004
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DOI: 10.1038/nature02764

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