MAP kinase phosphatase-2 plays a critical role in response to infection by Leishmania mexicana

Abstract

In this study we generated a novel dual specific phosphatase 4 (DUSP4) deletion mouse using a targeted deletion strategy in order to examine the role of MAP kinase phosphatase-2 (MKP-2) in immune responses. Lipopolysaccharide (LPS) induced a rapid, time and concentration-dependent increase in MKP-2 protein expression in bone marrow-derived macrophages from MKP-2+/+ but not from MKP-22/2 mice. LPS-induced JNK and p38 MAP kinase phosphorylation was significantly increased and prolonged in MKP-22/2 macrophages whilst ERK phosphorylation was unaffected. MKP-2 deletion also potentiated LPS-stimulated induction of the inflammatory cytokines, IL-6, IL-12p40, TNF-a, and also COX-2 derived PGE2 production. However surprisingly, in MKP-22/2 macrophages, there was a marked reduction in LPS or IFNc-induced iNOS and nitric oxide release and enhanced basal expression of arginase-1, suggesting that MKP-2 may have an additional regulatory function significant in pathogen-mediated immunity.