title: 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-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 PGE(2) production. However surprisingly, in MKP-2(-/-) macrophages, there was a marked reduction in LPS or IFNγ-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.
authors.affiliation: Division of Physiology & Pharmacology, Strathclyde Institute of Pharmacy & Biomedical Sciences, University of Strathclyde, Glasgow, United Kingdom.
authors.forename: Mashael S
authors.initials: MS
authors.lastname: Al-Mutairi
authors.forename: Laurence C
authors.initials: LC
authors.lastname: Cadalbert
authors.forename: H Adrienne
authors.initials: HA
authors.lastname: McGachy
authors.forename: Muhannad
authors.initials: M
authors.lastname: Shweash
authors.forename: Juliane
authors.initials: J
authors.lastname: Schroeder
authors.forename: Magdalena
authors.initials: M
authors.lastname: Kurnik
authors.forename: Callum M
authors.initials: CM
authors.lastname: Sloss
authors.forename: Clare E
authors.initials: CE
authors.lastname: Bryant
authors.forename: James
authors.initials: J
authors.lastname: Alexander
authors.forename: Robin
authors.initials: R
authors.lastname: Plevin
mesh_terms: D000818:Animals; D001119:Arginase / Q000378:metabolism; D015153:Blotting, Western; D001853:Bone Marrow / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D018836:Inflammation Mediators / Q000378:metabolism*; D007894:Leishmania mexicana / Q000472:pathogenicity*; D016773:Leishmaniasis, Cutaneous / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D009569:Nitric Oxide; D048051:p38 Mitogen-Activated Protein Kinases; C522186:Dusp4 protein, mouse; D017027:Protein Tyrosine Phosphatases; D001119:Arginase