title: Leishmania promastigotes selectively inhibit interleukin 12 induction in bone marrow-derived macrophages from susceptible and resistant mice.
abstract: Leishmania major promastigotes were found to avoid activation of mouse bone marrow-derived macrophages (BMM0) in vitro for production of cytokines that are typically induced during infection with other intracellular pathogens. Coexposure of BMM0 to the parasite and other microbial stimuli resulted in complete inhibition of interleukin (IL) 12 (p40) mRNA induction and IL-12 release. In contrast, mRNA and protein levels for IL-1(alpha), IL-1(beta), tumor necrosis factor (TNF) alpha, and inducible NO synthase (iNOS) were only partially reduced, and signals for IL-10 and monocyte chemoattractant protein (MCP-1/JE) were enhanced. The parasite could provide a detectable trigger for TNF-alpha and iNOS in BMM0 primed with interferon (IFN) gamma, but still failed to induce IL-12. Thus IL-12 induction is selectively impaired after infection, whereas activation pathways for other monokine responses remain relatively intact. Selective and complete inhibition of IL-12(p40) induction was observed using BMM0 from either genetically susceptible or resistant mouse strains, as well as IL-10 knockout mice, and was obtained using promastigotes from cutaneous, visceral, and lipophosphoglycan-deficient strains of Leishmania. The impaired production of the major physiological inducer of IFN-gamma is suggested to underlie the relatively prolonged interval of parasite intracellular survival and replication that is typically associate with leishmanial infections, including those producing self-limiting disease.
authors.affiliation: Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: L
authors.initials: L
authors.lastname: Carrera
authors.forename: R T
authors.initials: RT
authors.lastname: Gazzinelli
authors.forename: R
authors.initials: R
authors.lastname: Badolato
authors.forename: S
authors.initials: S
authors.lastname: Hieny
authors.forename: W
authors.initials: W
authors.lastname: Muller
authors.forename: R
authors.initials: R
authors.lastname: Kuhn
authors.forename: D L
authors.initials: DL
authors.lastname: Sacks
mesh_terms: D000818:Animals; D001483:Base Sequence; D001853:Bone Marrow / Q000276:immunology*; D001854:Bone Marrow Cells; D016207:Cytokines / Q000096:biosynthesis; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D007113:Immunity, Innate / Q000235:genetics; D018664:Interleukin-12 / Q000096:biosynthesis* / Q000235:genetics; D007891:Leishmania / Q000276:immunology*; D007893:Leishmania donovani / Q000276:immunology; D018320:Leishmania major / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009169:Mycobacterium tuberculosis / Q000276:immunology; D012333:RNA, Messenger / Q000032:analysis
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D018664:Interleukin-12