Nitric oxide inhibits IgE-mediated degranulation of mast cells and is the principal intermediate in IFN-gamma-induced suppression of exocytosis.
IFN-gamma regulates various aspects of rodent peritoneal mast cell function, including mediator release, cell growth, TNF-alpha-mediated cytotoxicity, and MHC class II expression. We investigated whether the suppressive action of IFN-gamma on IgE/Ag-mediated degranulation of mast cells is mediated via synthesis of nitric oxide. Incubation of mouse peritoneal cells with L-NMMA, an inhibitor of nitric oxide synthase, or in medium lacking the nitric oxide precursor L-arginine reversed the inhibitory effect of IFN-gamma on Ag-induced serotonin release. Furthermore, the nitric oxide donors sodium nitroprusside and S-nitrosoglutathione inhibited degranulation, and this effect was direct, since it was seen equally on purified and unfractionated mast cells and occurred independently of IFN-gammaR expression. Additional experiments revealed that accessory cells in peritoneal cell populations were the principal target for the action of IFN-gamma and the main source of nitric oxide; the cytokine was more potent on unfractionated compared with purified mast cells, and IFN-gamma induced detectable nitrite production in mixed peritoneal cells, but not in purified mast cells. These studies 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 important in the control of mast cell-dependent allergic reactions.
Eastmond
N C
NC
Department of Pharmacology and Therapeutics, University of Liverpool, United Kingdom. nce@liv.ac.uk
Banks
E M
EM
Coleman
J W
JW
D000818:Animals; D001120:Arginine / Q000378:metabolism; D015550:Cell Degranulation / Q000187:drug effects / Q000276:immunology*; D002469:Cell Separation; D005089:Exocytosis / Q000187:drug effects / Q000276:immunology*; D005260:Female; D017353:Gene Deletion; D005978:Glutathione / Q000031:analogs & derivatives / Q000494:pharmacology; D007073:Immunoglobulin E / Q000502:physiology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D008407:Mast Cells / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000096:biosynthesis / Q000737:chemistry / Q000494:pharmacology*; D009573:Nitrites / Q000378:metabolism; D009599:Nitroprusside / Q000494:pharmacology; D009603:Nitroso Compounds / Q000494:pharmacology; D017471:Receptors, Interferon / Q000235:genetics; D026422:S-Nitrosoglutathione; D019323:omega-N-Methylarginine / Q000494:pharmacology; D000096743:Interferon gamma Receptor
D001120:Arginine; D005978:Glutathione; D007073:Immunoglobulin E; D007166:Immunosuppressive Agents; D007371:Interferon-gamma; D009569:Nitric Oxide; D009573:Nitrites; D009599:Nitroprusside; D009603:Nitroso Compounds; D017471:Receptors, Interferon; D026422:S-Nitrosoglutathione; D019323:omega-N-Methylarginine; D000096743:Interferon gamma Receptor