title: Blockage of Eosinopoiesis by IL-17A Is Prevented by Cytokine and Lipid Mediators of Allergic Inflammation.
abstract: Interleukin- (IL-) 17A, a pleiotropic mediator of inflammation and autoimmunity, potently stimulates bone-marrow neutrophil production. To explore IL-17A effects on eosinopoiesis, we cultured bone-marrow from wild-type mice, or mutants lacking inducible nitric oxide synthase (iNOS-/-), CD95 (lpr), IL-17RA, or IL-4, with IL-5, alone or associated with IL-17A. Synergisms between IL-17A-activated, NO-dependent, and NO-independent mechanisms and antagonisms between IL-17A and proallergic factors were further examined. While IL-17A (0.1-10 ng/mL) had no IL-5-independent effect on eosinopoiesis, it dose-dependently suppressed IL-5-induced eosinophil differentiation, by acting during the initial 24 hours. Its effectiveness was abolished by caspase inhibitor, zVAD-fmk. The effect of IL-17A (0.1-1 ng/mL) was sensitive to the iNOS-selective inhibitor aminoguanidine and undetectable in iNOS-/- bone-marrow. By contrast, a higher IL-17A concentration (10 ng/mL) retained significant suppressive effect in both conditions, unmasking a high-end iNOS-independent mechanism. Lower IL-17A concentrations synergized with NO donor nitroprusside. Eosinopoiesis suppression by IL-17A was (a) undetectable in bone-marrow lacking IL-17RA or CD95 and (b) actively prevented by LTD4, LTC4, IL-13, and eotaxin. Sensitivity to IL-17A was increased in bone-marrow lacking IL-4; adding IL-4 to the cultures restored IL-5 responses to control levels. Therefore, effects of both IL-17A and proallergic factors are transduced by the iNOS-CD95 pathway in isolated bone-marrow.
authors.affiliation: Department of Immunology, Paulo de Góes Institute for Microbiology, Federal University of Rio de Janeiro (UFRJ), 21941-590 Rio de Janeiro, RJ, Brazil.
authors.forename: Pedro
authors.initials: P
authors.lastname: Xavier-Elsas
authors.affiliation: Department of Pediatrics, Fernandes Figueira National Institute for Health of Women, Children and Adolescents, Oswaldo Cruz Foundation (FIOCRUZ), 22250-020 Rio de Janeiro, RJ, Brazil.
authors.forename: Bianca
authors.initials: B
authors.lastname: de Luca
authors.affiliation: Department of Pediatrics, Fernandes Figueira National Institute for Health of Women, Children and Adolescents, Oswaldo Cruz Foundation (FIOCRUZ), 22250-020 Rio de Janeiro, RJ, Brazil.
authors.forename: Túlio
authors.initials: T
authors.lastname: Queto
authors.affiliation: Department of Pediatrics, Fernandes Figueira National Institute for Health of Women, Children and Adolescents, Oswaldo Cruz Foundation (FIOCRUZ), 22250-020 Rio de Janeiro, RJ, Brazil.
authors.forename: Bruno Marques
authors.initials: BM
authors.lastname: Vieira
authors.affiliation: Department of Immunology, Paulo de Góes Institute for Microbiology, Federal University of Rio de Janeiro (UFRJ), 21941-590 Rio de Janeiro, RJ, Brazil.
authors.forename: Daniela
authors.initials: D
authors.lastname: Masid-de-Brito
authors.affiliation: Department of Immunology, Paulo de Góes Institute for Microbiology, Federal University of Rio de Janeiro (UFRJ), 21941-590 Rio de Janeiro, RJ, Brazil.
authors.forename: Elizabeth Chen
authors.initials: EC
authors.lastname: Dahab
authors.affiliation: Department of Pharmacology, Medical School of Ribeirão Preto, University of São Paulo, 14049-900 Ribeirão Preto, SP, Brazil.
authors.forename: José Carlos
authors.initials: JC
authors.lastname: Alves Filho
authors.affiliation: Department of Pharmacology, Medical School of Ribeirão Preto, University of São Paulo, 14049-900 Ribeirão Preto, SP, Brazil.
authors.forename: Fernando Q
authors.initials: FQ
authors.lastname: Cunha
authors.affiliation: Department of Pediatrics, Fernandes Figueira National Institute for Health of Women, Children and Adolescents, Oswaldo Cruz Foundation (FIOCRUZ), 22250-020 Rio de Janeiro, RJ, Brazil.
authors.forename: Maria Ignez C
authors.initials: MI
authors.lastname: Gaspar-Elsas
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D016207:Cytokines / Q000494:pharmacology*; D004804:Eosinophils / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006967:Hypersensitivity / Q000188:drug therapy*; D007249:Inflammation / Q000378:metabolism; D018793:Interleukin-13 / Q000494:pharmacology; D020381:Interleukin-17 / Q000494:pharmacology*; D015847:Interleukin-4 / Q000494:pharmacology; D015848:Interleukin-5 / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C
chemical_list: D016207:Cytokines; D018793:Interleukin-13; D020381:Interleukin-17; D015848:Interleukin-5; D015847:Interleukin-4