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

摘要

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 in-domethacin, 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.