title: Leishmania major inhibits IL-12 in macrophages by signalling through CR3 (CD11b/CD18) and down-regulation of ETS-mediated transcription.
abstract: Leishmania major is an aetiological agent of cutaneous leishmaniasis. The parasite primarily infects immune sentinel cells, specifically macrophages and dendritic cells, in the mammalian host. Infection is receptor mediated and is known to involve parasite binding to cell surface protein complement receptor 3 (CR3, Mac-1, CD11b/CD18). Engagement of CR3 by various ligands inhibits production of interleukin-12 (IL-12), the cytokine that drives antileishmanial T helper 1-type immune responses. Likewise, L. major infection inhibits IL-12 production and activation of host macrophages. Our data indicate that in the absence of CR3, L. major-infected bone marrow-derived macrophages produce more IL-12 and nitric oxide compared with WT cells upon lipopolysaccharide (LPS) stimulation. We therefore investigated multiple signalling pathways by which L. major may inhibit IL-12 transcription through CR3 ligation. We demonstrate that L. major infection does not elicit significant NFκB p65, MAPK, IRF-1 or IRF-8 activation in WT or CD11b-deficient macrophages. Furthermore, infection neither inhibits LPS-induced MAPK or NFκB activation nor blocks IFN-γ-activated IRF-1 and IRF-8. ETS-mediated transcription, however, is inhibited by L. major infection independently of CR3. Our data indicate that L. major-mediated inhibition of IL-12 occurs through CR3 engagement; however, the mechanism of inhibition is independent of NFκB, MAPK, IRF and ETS.
authors.affiliation: Eck Institute for Global Health, Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA.
authors.forename: C
authors.initials: C
authors.lastname: Ricardo-Carter
authors.forename: M
authors.initials: M
authors.lastname: Favila
authors.forename: R E
authors.initials: RE
authors.lastname: Polando
authors.forename: R N
authors.initials: RN
authors.lastname: Cotton
authors.forename: K
authors.initials: K
authors.lastname: Bogard Horner
authors.forename: D
authors.initials: D
authors.lastname: Condon
authors.forename: W
authors.initials: W
authors.lastname: Ballhorn
authors.forename: J P
authors.initials: JP
authors.lastname: Whitcomb
authors.forename: M
authors.initials: M
authors.lastname: Yadav
authors.forename: R L
authors.initials: RL
authors.lastname: Geister
authors.forename: J S
authors.initials: JS
authors.lastname: Schorey
authors.forename: M A
authors.initials: MA
authors.lastname: McDowell
mesh_terms: D000818:Animals; D015536:Down-Regulation; D005786:Gene Expression Regulation; D050856:Interferon Regulatory Factor-1 / Q000378:metabolism; D050835:Interferon Regulatory Factors / Q000378:metabolism; D018664:Interleukin-12 / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D018320:Leishmania major / Q000235:genetics / Q000276:immunology* / Q000502:physiology*; D016773:Leishmaniasis, Cutaneous / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology; D008070:Lipopolysaccharides / Q000276:immunology; D016177:Macrophage-1 Antigen / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology*; D051379:Mice; D008807:Mice, Inbred BALB C; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D000099185:Interferon Regulatory Factor-8
chemical_list: D050856:Interferon Regulatory Factor-1; D050835:Interferon Regulatory Factors; D018664:Interleukin-12; D008070:Lipopolysaccharides; D016177:Macrophage-1 Antigen; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D009569:Nitric Oxide; D000099185:Interferon Regulatory Factor-8; C494258:Irf1 protein, mouse
keywords: CR3; ETS; Leishmania major; signal transduction