Pro-Th1 cytokines promote Fas-dependent apoptosis of immature peripheral basophils.
We have previously characterized immature hemopoietic cells of the basophil lineage as a lin(-)c-kit(-) population, which responds to IL-3 by enhancing its histamine synthesis through histidine decarboxylase activation. Herein, we show both in vitro and in vivo that exposure to the pro-Th1 cytokines IL-12 and IL-18 promotes Fas-dependent apoptosis of these cells in the spleen. This conclusion was supported by the following findings: 1) A 24-h treatment with IL-12 plus IL-18 enhanced Fas expression and annexin staining among basophil precursor-enriched lin(-)c-kit(-) splenocytes. 2) Fas or Fas ligand deficiency in mutant mice abolished the inhibitory effect of IL-12 plus IL-18 on IL-3-induced histamine production. 3) The large spectrum inhibitor of the caspase cascade, benzyloxycarbonyl-Val-Ala-Asp fluoromethylketone, significantly reduced the effect of IL-12 plus IL-18. The inhibition of histamine production was mediated through NK cells, since it failed to occur upon stimulation of spleen cells from NK cell-deficient mice or after NK cell depletion. IL-12 plus IL-18 rendered NK cells cytotoxic against Fas-transfected target cells and promoted their production of IFN-gamma and TNF-alpha, which are both essential for sensitizing histamine-producing cells to the Fas death pathway. This is the first evidence that pro-Th1 cytokines can promote apoptosis of immature peripheral histamine-producing cells, thus limiting Th2 immune responses. Comparable in vivo data as well as increased histamine production in the spleen of aged Fas-deficient lpr mice support its physiological relevance.
Schneider
Elke
E
Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8147, Université René Descartes-Paris V, Institut Necker, Paris, France. schneider@necker.fr
Tonanny
Marie-Béatrice
MB
Lisbonne
Mariette
M
Leite-de-Moraes
Maria
M
Dy
Michel
M
D000818:Animals; D000941:Antigens / Q000096:biosynthesis; D000954:Antigens, Surface; D017209:Apoptosis / Q000276:immunology*; D001491:Basophils / Q000166:cytology* / Q000276:immunology*; D016923:Cell Death / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis / Q000502:physiology*; D003601:Cytotoxicity Tests, Immunologic; D015536:Down-Regulation / Q000276:immunology; D004338:Drug Combinations; D005260:Female; D006632:Histamine / Q000096:biosynthesis; D006633:Histamine Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D006636:Histamine Release / Q000276:immunology; D007275:Injections, Intravenous; D007371:Interferon-gamma / Q000096:biosynthesis / Q000502:physiology; D018664:Interleukin-12 / Q000008:administration & dosage / Q000494:pharmacology; D020382:Interleukin-18 / Q000008:administration & dosage / Q000494:pharmacology; D007377:Interleukin-3 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D037181:Lectins, C-Type; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D055651:NK Cell Lectin-Like Receptor Subfamily B; D014176:Protein Biosynthesis; D011506:Proteins; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000502:physiology; D019014:fas Receptor / Q000235:genetics / Q000502:physiology*
D000941:Antigens; D000954:Antigens, Surface; D016207:Cytokines; D004338:Drug Combinations; D006633:Histamine Antagonists; D020382:Interleukin-18; D007377:Interleukin-3; D037181:Lectins, C-Type; D055651:NK Cell Lectin-Like Receptor Subfamily B; D011506:Proteins; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D018664:Interleukin-12; D006632:Histamine; D007371:Interferon-gamma