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The Journal of Immunology, 2008, 181, 7689-7698
Copyright © 2008 by The American Association of Immunologists, Inc.
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Retinoic Acids Are Potent Inhibitors of Spontaneous Human Eosinophil Apoptosis

Shigeharu Ueki1, Gulixian Mahemuti1, Hajime Oyamada, Hikari Kato, Junko Kihara, Masako Tanabe, Wataru Ito, Takahito Chiba, Masahide Takeda, Hiroyuki Kayaba and Junichi Chihara2

Department of Clinical and Laboratory Medicine, Akita University School of Medicine, Akita, Japan

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 (10–6M) 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 S.U. and G.M. contributed equally to this study.

2 Address correspondence and reprint requests to Dr. Junichi Chihara, Department of Clinical and Laboratory Medicine, Akita University School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan. E-mail address: chihara{at}hos.akita-u.ac.jp

3 Abbreviations used in this paper: RA, retinoic acid; ATRA, all-trans RA; MFI, mean fluorescence intensity; PPAR{gamma}, peroxisome proliferator-activated receptor {gamma}; RAR, RA receptor; RXR, retinoid X receptor; PI, propidium iodide; VEGF, vascular endothelial growth factor; RT, reverse transcriptase; TTNPB, [(E)-2–2(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl]benzoic acid.






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