title: Retinoic acids are potent inhibitors of spontaneous human eosinophil apoptosis.
abstract: Retinoic acids (RAs), which are active metabolites of vitamin A, are known to enhance Th2-type immune responses in vitro, but the role of RAs in allergic inflammatory cells remains unclear. In this study, we demonstrated that purified peripheral blood eosinophils expressed nuclear receptors for RAs at the mRNA and protein levels. Eosinophils cultured with all-trans RA (ATRA) and 9-cis-RA showed dramatically induced cell survival and nuclear hypersegmentation, and the efficacy of RAs (10(-6)M) was similar to that of IL-5 (1 ng/ml), the most critical cytokine for eosinophil activation. Pharmacological manipulation with receptor-specific agonists and antagonists indicated that the antiapoptotic effect of RAs was mediated through ligand-dependent activation of both retinoid acid receptors and retinoid X receptors (mainly retinoid acid receptors). Furthermore, using a gene microarray and a cytokine Ab array, we discovered that RAs induced vascular endothelial growth factor, M-CSF, and MCP-1 secretion, although they were not involved in eosinophil survival. RA-induced eosinophil survival appears to be associated with down-regulation of caspase 3 and inhibition of its enzymatic activity. These findings indicate an important role of RAs in homeostasis of granulocytes and provide further insight into the cellular and molecular pathogenesis of allergic reactions.
authors.affiliation: Department of Clinical and Laboratory Medicine, Akita University School of Medicine, Akita, Japan.
authors.forename: Shigeharu
authors.initials: S
authors.lastname: Ueki
authors.forename: Gulixian
authors.initials: G
authors.lastname: Mahemuti
authors.forename: Hajime
authors.initials: H
authors.lastname: Oyamada
authors.forename: Hikari
authors.initials: H
authors.lastname: Kato
authors.forename: Junko
authors.initials: J
authors.lastname: Kihara
authors.forename: Masako
authors.initials: M
authors.lastname: Tanabe
authors.forename: Wataru
authors.initials: W
authors.lastname: Ito
authors.forename: Takahito
authors.initials: T
authors.lastname: Chiba
authors.forename: Masahide
authors.initials: M
authors.lastname: Takeda
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kayaba
authors.forename: Junichi
authors.initials: J
authors.lastname: Chihara
mesh_terms: D000970:Antineoplastic Agents / Q000276:immunology / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D053148:Caspase 3 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D002467:Cell Nucleus / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D018932:Chemokine CCL2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D016228:Endothelial Growth Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004804:Eosinophils / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D006706:Homeostasis / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D006801:Humans; D006967:Hypersensitivity / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015848:Interleukin-5 / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008297:Male; D040081:Protein Array Analysis; D047488:Retinoid X Receptors / Q000819:agonists / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014212:Tretinoin / Q000276:immunology / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D016228:Endothelial Growth Factors; C508599:IL5 protein, human; D015848:Interleukin-5; D047488:Retinoid X Receptors; D014212:Tretinoin; D016173:Macrophage Colony-Stimulating Factor; C505409:Casp3 protein, mouse; D053148:Caspase 3