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

Abstract

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.

Dual-Specificity Phosphatase 14 (DUSP14/MKP6) Negatively Regulates TCR Signaling by Inhibiting TAB1 Activation

“…Only two DUSPs (DUSP4 and DUSP10) are reported to be involved in T cell activation and T cell-mediated immune responses using KO mice (21)(22)(23). DUSP10 (also named MKP5) is a positive regulator in T cell proliferation and T cell-mediated immune responses (22).…”

“…Only two DUSPs (DUSP4 and DUSP10) are reported to be involved in T cell activation and T cell-mediated immune responses using KO mice (21)(22)(23). DUSP10 (also named MKP5) is a positive regulator in T cell proliferation and T cell-mediated immune responses (22). DUSP4 (also named MKP2) suppresses CD4 + T cell proliferation but induces normal Th1/Th2 responses following KLH immunization (23), whereas DUSP4 enhances Th1 responses following Leishmania mexicana infection (21).…”

Synergistic induction of tissue factor by coagulation factor Xa and TNF: Evidence for involvement of negative regulatory signaling cascades

“…The inhibition of MKP-5 by fXa is particularly noteworthy, because MKP-5 was recently shown to play a principal role in innate and adaptive immune responses. JNK activity is selectively increased in MKP-5-deficient cells that produce greatly enhanced levels of proinflammatory cytokines (38).…”

Regulation of Adipose Tissue Inflammation and Insulin Resistance by MAPK Phosphatase 5

“…We previously found that one MKP protein family member, MKP5, inhibits proinflammatory cytokine production in both innate and adaptive immune responses (16). MKP5 is abundantly expressed in insulin responsive tissues and organs such as skeletal muscle and liver in both human and mouse (17,18).…”