NITRIC-OXIDE INHIBITS IGE-MEDIATED DEGRANULATION OF MAST-CELLS AND ISTHE PRINCIPAL INTERMEDIATE IN IFN-GAMMA-INDUCED SUPPRESSION OF EXOCYTOSIS

IFN-gamma regulates various aspects of rodent peritoneal mast cell fun ction, including mediator release, cell growth, TNF-alpha-mediated cyt otoxicity, and MHC class II expression, We investigated whether the su ppressive action of IFN-gamma an IgE/Ag-mediated degranulation of mast cells is mediated via synthesis of nitric oxide, Incubation a: mouse peritoneal cells with L-NMMA, an inhibitor of nitric oxide synthase, o r in medium lacking the nitric oxide precursor L-arginine reversed the inhibitory effect of IFN-gamma on Ag-induced serotonin release. Furth ermore, the nitric oxide donors sodium nitroprusside and S-nitrosoglut athione inhibited degranulation, and this effect was direct, since it was seen equally on purified and unfractionated mast cells and occurre d independently of IFN-gamma R expression, Additional experiments reve aled that accessory cells in peritoneal cell populations were the prin cipal target for the action of IFN-gamma and the main source of nitric oxide; the cytokine was more potent on unfractionated compared with p urified mast cells, and IFN-gamma induced detectable nitrite productio n in mixed peritoneal cells, hut not in purified mast cells, These stu dies show that IFN-gamma induces nitric oxide production in peritoneal cell populations, and that synthesized nitric oxide directly inhibits the IgE-mediated secretory function of mast cells, The activation of nitric oxide producing cells in the tissue microenvironment may be imp ortant in the control of mast cell-dependent allergic reactions.