title: Novel lineage- and stage-selective effects of retinoic acid on mouse granulopoiesis: Blockade by dexamethasone or inducible NO synthase inactivation.
abstract: Despite the close relationship of eosinophils and neutrophils, these granulocyte lineages respond to distinct cytokines and play unique roles in immune responses. They nevertheless respond to shared physiological/pharmacological regulators, including glucocorticoids and retinoids, and to ubiquitous mediators, including NO. Others showed that, in humans, all-trans retinoic acid (ATRA) suppresses eosinophil differentiation, but promotes neutrophil differentiation. Mechanisms of dual co-regulation of physiological granulopoiesis were here examined in murine bone-marrow, a model system suitable for exploration of immunopharmacological mechanisms, given the availability of experimental resources, including mutant/knockout mouse strains. We examined the effects of ATRA on mouse eosinophil and neutrophil production, using wild-type (BALB/c, C57BL/6) and mutant (iNOS-, CD95L-, or CD95-KO) bone-marrow cultures, further assessing the modification of ATRA activity by dexamethasone and iNOS blockade. ATRA (10-6-10-8M) significantly decreased eosinophil production relative to IL-5 controls. This effect was iNOS-independent, but CD95L- and caspase-dependent, and prevented by dexamethasone (10-7M in vitro; 1-20mg·kg-1in vivo). In myeloid colony formation assays, ATRA markedly suppressed GM-CSF-responsive progenitors, through an iNOS-dependent, CD95-independent, dexamethasone-sensitive mechanism. By contrast, ATRA potently enhanced GM-CSF-dependent neutropoiesis in liquid culture from BALB/c or C57BL/6 bone-marrow. This novel stimulatory effect was resistant to dexamethasone and abolished in iNOS-KO bone-marrow. ATRA injections also induced lineage- and stage-selective effects on granulopoiesis in vivo. ATRA therefore co-regulates eosinophil and neutrophil production in murine bone-marrow through multiple lineage- and stage-selective mechanisms.
authors.affiliation: Dept. Immunology, Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, RJ, Brazil. Electronic address: pxelsas@micro.ufrj.br.
authors.forename: Pedro
authors.initials: P
authors.lastname: Xavier-Elsas
authors.affiliation: Dept. Pediatrics, Instituto Nacional de Saúde da Mulher, da Criança e do Adolescente Fernandes Figueira, FIOCRUZ, RJ, Brazil.
authors.forename: Bruno Marques
authors.initials: BM
authors.lastname: Vieira
authors.affiliation: Dept. Immunology, Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, RJ, Brazil.
authors.forename: Daniela
authors.initials: D
authors.lastname: Masid-de-Brito
authors.affiliation: Dept. Immunology, Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, RJ, Brazil.
authors.forename: Juliana
authors.initials: J
authors.lastname: Santos
authors.affiliation: Dept. Pediatrics, Instituto Nacional de Saúde da Mulher, da Criança e do Adolescente Fernandes Figueira, FIOCRUZ, RJ, Brazil.
authors.forename: Monica Gomes
authors.initials: MG
authors.lastname: Barradas
authors.affiliation: Dept. Pediatrics, Instituto Nacional de Saúde da Mulher, da Criança e do Adolescente Fernandes Figueira, FIOCRUZ, RJ, Brazil.
authors.forename: Bianca
authors.initials: B
authors.lastname: de Luca
authors.affiliation: Dept. Pediatrics, Instituto Nacional de Saúde da Mulher, da Criança e do Adolescente Fernandes Figueira, FIOCRUZ, RJ, Brazil.
authors.forename: Maria Ignez
authors.initials: MI
authors.lastname: Gaspar-Elsas
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001854:Bone Marrow Cells / Q000187:drug effects* / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology*; D004804:Eosinophils / Q000187:drug effects* / Q000502:physiology; D053222:Fas Ligand Protein / Q000235:genetics / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006410:Hematopoiesis / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000187:drug effects* / Q000502:physiology; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism*; D009928:Organ Specificity; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D053222:Fas Ligand Protein; D014212:Tretinoin; D003907:Dexamethasone; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D052247:Nitric Oxide Synthase Type II
keywords: ATRA; Dexamethasone; Eosinophil; Inducible NO synthase; Neutrophil