Prostaglandin E2 and dexamethasone regulate eosinophil differentiation and survival through a nitric oxide- and CD95-dependent pathway.
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 E2 (PGE2) 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 PGE2, dexamethasone or both. PGE2 (10(-7)M) inhibited eosinophil differentiation by selectively inducing apoptosis in developing eosinophils. Dexamethasone (10(-7)M) protected developing eosinophils from PGE2-induced apoptosis. Since dexamethasone prevents induction of nitric oxide synthase (NOS), we evaluated the role of NO in the effects of both PGE2 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, Nomega-nitro-L-arginine and aminoguanidine, blocked the effects of PGE2 on developing eosinophils. PGE2 was ineffective in bone-marrow from knockout mice lacking inducible NOS. PGE2 up-regulated CD95 and CD95L expression in developing eosinophils. Neither PGE2 nor SNAP were effective in cultures from CD95L-deficient gld mice. These data suggest that PGE2 induces apoptosis in developing eosinophils through inducible NOS, leading to NO-dependent activation of the CD95L/CD95 pathway, while dexamethasone antagonizes the effects of PGE2 on the same targets.
Jones
Carla P
CP
Department of Immunology, Professor Paulo de Góes Institute of Microbiology, Federal University of Rio de Janeiro, Brazil.
Paula Neto
Heitor A
HA
Assreuy
Jamil
J
Vargaftig
B Boris
BB
Gaspar Elsas
Maria Ignez
MI
Elsas
P Xavier
PX
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001854:Bone Marrow Cells; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology*; D015232:Dinoprostone / Q000494:pharmacology*; D004336:Drug Antagonism; D004804:Eosinophils / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D053222:Fas Ligand Protein; D005260:Female; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D019014:fas Receptor / Q000378:metabolism
D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D019014:fas Receptor; D009569:Nitric Oxide; D003907:Dexamethasone; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D015232:Dinoprostone