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Novel Pathway for Control of Eosinophil Differentiation by Drugs, Cytokines, and Allergen

¹ Department of Immunology, IMPPG-UFRJ, Rio de Janeiro, Brazil; ² Department of Pediatrics, IFF-FIOCRUZ, Rio de Janeiro, Brazil; ³ Department of Pharmacology, FMRP-USP, São Paulo, Brazil; and ⁴ Brigham and Women's Hospital, Boston, Massachusetts

Correspondence and requests for reprints should be addressed to Pedro Xavier-Elsas, M.D., Ph.D., Associate Professor, Dept. Immunology, Instituto de Microbiologia Prof. Paulo de Góes, Universidade Federal do Rio de Janeiro, CCS Bloco I, 2nd floor, Room I-2-066, CEP 21941-590, Rio de Janeiro, Brazil. E-mail: pxelsas{at}yahoo.com.br

Eosinophilopoiesis in the bone marrow (BM), which maintains chronic inflammation in asthma, is externally controlled through a novel pro-apoptotic pathway. Prostaglandin E2 (PGE2) induces apoptosis in eosinophils developing in IL-5–stimulated murine BM cultures. This effect is duplicated by other cAMP-elevating agents, acting at surface receptors, or bypassing receptor activation. Apoptosis depends on inducible NO synthase (iNOS) expression, as BM from iNOS-KO mice, or wild-type BM in the presence of iNOS inhibitors, is resistant to all these agents, but sensitive to NO-releasing chemicals. BM from gld mice, which lack a functional CD95-CD95L death receptor pathway, resists all of the preceding treatments. Hence, CD95 acts downstream from iNOS. Aspirin and indomethacin, which enhance eosinophil production in IL-5–stimulated BM cultures, prevent apoptosis induction by PGE2, showing that they do not act through blockade of PGE2 production alone. Their effects are duplicated by exogenous cysteinyl-leukotrienes (Cys-LT). All of these enhancing agents act through type I Cys-LT receptors, as shown by the use of specific antagonists and of receptor-deficient mice. Aspirin and indomethacin induce endogenous Cys-LT production in BM culture, as shown by complete blockade of their effects by targeting 5-lipoxygenase (5-LO) and the 5-LO–activating protein, or by using 5-LO–deficient mice. Eotaxin and IL-13 also enhance eosinophilopoiesis through endogenous Cys-LT production. Aspirin, indomethacin, eotaxin, and IL-13 no longer modulate eosinophilopoiesis in BM from allergen-sensitized mice. This immunoregulatory effect is accounted for by loss of responsiveness to the effects of Cys-LT. Hence, COX and 5-LO products deliver death and survival signals, respectively, and cooperatively regulate eosinophilopoiesis in response to systemic signals.

FOOTNOTES

Supported by NIH (grant number HL082695 to B.K.L.), CNPq (Grants 474979/2004-0, 471176/2007-9, and 478253/2008-7 to P.X.-E. and M.I.G.-E.), and Research Productivity Fellowships to P.X.-E., M.I.G.-E., F.Q.C.), and FAPERJ (APQ1 grant number E-26/110.188/2008 to P.X.-E.), as well as by FIOCRUZ.

Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

(Received in original form November 26, 2008; accepted in final form November 26, 2008)

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