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.
CITATION STYLE
Al-Mutairi, M. S., Cadalbert, L. C., Adrienne McGachy, H., Shweash, M., Schroeder, J., Kurnik, M., … Plevin, R. (2010). MAP kinase phosphatase-2 plays a critical role in response to infection by Leishmania mexicana. PLoS Pathogens, 6(11). https://doi.org/10.1371/journal.ppat.1001192
Mendeley helps you to discover research relevant for your work.