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

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-2-/- mice. lps-induced jnk and p38 map kinase phosphorylation was significantly increased and prolonged in mkp-2-/- macrophages whilst erk phosphorylation was unaffected. mkp-2 deletion also potentiated lps-stimulated induction of the inflammatory cytokines,il-6,il-12p40,tnf-α,and also cox-2 derived pge2 production. however surprisingly,in mkp-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. indeed,following infection with the intracellular parasite leishmania mexicana,mkp-2-/- mice displayed increased lesion size and parasite burden,and a significantly modified th1/ th2 bias compared with wild-type counterparts. however,there was no intrinsic defect in mkp-2-/- t cell function as measured by anti-cd3 induced ifn-γ production. rather,mkp-2-/- bone marrow-derived macrophages were found to be inherently more susceptible to infection with leishmania mexicana,an effect reversed following treatment with the arginase inhibitor nor-noha. these findings show for the first time a role for mkp-2 in vivo and demonstrate that mkp-2 may be essential in orchestrating protection against intracellular infection at the level of the macrophage. © 2010 al-mutairi et al.