title: CD40-modulated dual-specificity phosphatases MAPK phosphatase (MKP)-1 and MKP-3 reciprocally regulate Leishmania major infection.
abstract: The macrophage-expressed CD40 regulates immune responses to Leishmania major infection by reciprocal signaling through p38 MAPK and ERK1/2. CD40-induced IL-10 or IL-12 plays crucial roles in the promotion or protection from L. major infection, respectively. Because p38 MAPK and ERK1/2 are dephosphorylated by dual-specificity MAPK phosphatases (MKPs), we tested the role of CD40 in the regulation of MKPs in L. major infection. MKP-1 expression and activity increased whereas MKP-3 expression and activity decreased in virulent L. major-infected macrophages. CD40 differentially regulated the expression and activity of MKP-1 and MKP-3, which, in turn, reciprocally regulated CD40-induced p38 MAPK and ERK1/2 phosphorylation and effector functions in macrophages. Triptolide, an inhibitor of MKP-1 expression, and lentivirally expressed MKP-1 short hairpin RNA enhanced CD40-induced anti-leishmanial functions and significantly protected susceptible BALB/c mice from L. major infection. Similarly, lentivirally overexpressed MKP-3 significantly reduced disease progression and parasite burden in susceptible BALB/c mice. Thus, to our knowledge, our data show for the first time that CD40 reciprocally regulates MKP-1 and MKP-3 expression and activity while the MKPs contribute to the reciprocal CD40 signaling-regulated anti-leishmanial functions. The findings reveal a novel parasite-devised immune evasion strategy and an effective target to redirect CD40-regulated immune responses.
authors.affiliation: National Centre for Cell Science, Ganeshkhind, Pune 411007, India.
authors.forename: Neetu
authors.initials: N
authors.lastname: Srivastava
authors.forename: Raki
authors.initials: R
authors.lastname: Sudan
authors.forename: Bhaskar
authors.initials: B
authors.lastname: Saha
mesh_terms: D000818:Animals; D019013:CD40 Antigens / Q000276:immunology* / Q000378:metabolism; D004224:Diterpenes / Q000494:pharmacology; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics / Q000378:metabolism*; D054642:Dual Specificity Phosphatase 6 / Q000235:genetics / Q000378:metabolism*; D004852:Epoxy Compounds / Q000494:pharmacology; D057131:Immune Evasion; D016753:Interleukin-10 / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology; D018320:Leishmania major / Q000276:immunology* / Q000472:pathogenicity; D016773:Leishmaniasis, Cutaneous / Q000276:immunology* / Q000469:parasitology; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000276:immunology / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D010616:Phenanthrenes / Q000494:pharmacology; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D034741:RNA, Small Interfering; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D019013:CD40 Antigens; D004224:Diterpenes; D004852:Epoxy Compounds; D010616:Phenanthrenes; D034741:RNA, Small Interfering; D016753:Interleukin-10; D018664:Interleukin-12; C001899:triptolide; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D054638:Dual Specificity Phosphatase 1; D054642:Dual Specificity Phosphatase 6