Prostaglandin E2 and dexamethasone regulate eosinophil differentiation and survival through a nitric oxide- and CD95-dependent pathway

• Published in: Nitric oxide 2004-09, Vol.11 (2), p.184-193
• Main Authors: Jones, Carla P., Paula Neto, Heitor A., Assreuy, Jamil, Vargaftig, B. Boris, Gaspar Elsas, Maria Ignez, Elsas, P. Xavier
• Format: Article
• Language: English
• Subjects: Allergy; Animals; Apoptosis; Apoptosis - drug effects; Bone Marrow Cells; Cell Differentiation - drug effects; Cell Survival - drug effects; Cells, Cultured; Dexamethasone - pharmacology; Dinoprostone - pharmacology; Drug Antagonism; Eosinophils; Eosinophils - cytology; Eosinophils - drug effects; Eosinophils - metabolism; Fas Ligand Protein; fas Receptor - metabolism; Female; Hematopoiesis; Male; Membrane Glycoproteins - metabolism; Mice; Mice, Inbred BALB C; Mice, Knockout; Mice, Mutant Strains; Nitric oxide; Nitric Oxide - metabolism; Nitric Oxide Synthase - genetics; Nitric Oxide Synthase Type II
• ISSN: 1089-8603; 1089-8611
• DOI: 10.1016/j.niox.2004.08.001

Apoptosis, involving both CD95/CD95L interactions and their modulation by nitric oxide (NO), is central to regulation of mature eosinophil numbers. However, its role in regulating eosinophil production from bone-marrow precursors is unknown. We examined the effects of prostaglandin E 2 (PGE 2) and dexamethasone on eosinophil differentiation and survival in murine bone-marrow cultures, and their relationship to: NO production as well as CD95/CD95L-dependent apoptosis. Bone-marrow cultures were established with IL-5, alone or in association with PGE 2, dexamethasone or both. PGE 2 (10 −7 M) inhibited eosinophil differentiation by selectively inducing apoptosis in developing eosinophils. Dexamethasone (10 −7 M) protected developing eosinophils from PGE 2-induced apoptosis. Since dexamethasone prevents induction of nitric oxide synthase (NOS), we evaluated the role of NO in the effects of both PGE 2 and dexamethasone. NO donors (SNAP and SNP) down-modulated eosinophil precursor responses to IL-5. SNAP induced apoptosis through a dexamethasone-resistant mechanism. The NOS inhibitors, Nω-nitro- l-arginine and aminoguanidine, blocked the effects of PGE 2 on developing eosinophils. PGE 2 was ineffective in bone-marrow from knockout mice lacking inducible NOS. PGE 2 up-regulated CD95 and CD95L expression in developing eosinophils. Neither PGE 2 nor SNAP were effective in cultures from CD95L-deficient gld mice. These data suggest that PGE 2 induces apoptosis in developing eosinophils through inducible NOS, leading to NO-dependent activation of the CD95L/CD95 pathway, while dexamethasone antagonizes the effects of PGE 2 on the same targets.