title: Nitric oxide production is required for murine resident peritoneal macrophages to suppress mitogen-stimulated T cell proliferation. Role of IFN-gamma in the induction of the nitric oxide-synthesizing pathway.
abstract: Lymphocyte proliferation in Con A- or LPS-stimulated murine splenic cell (SC) cultures was suppressed by the addition of excess macrophages. In Con A-stimulated cultures, suppression was associated with the expression of nitric oxide-synthesizing pathway (NOSP) activity as demonstrated by the accumulation of nitrite, a degradation product of nitric oxide (NO), in the culture supernatants. That NO, a cytotoxic and anti-proliferative metabolite of l-arginine, or other reactive nitrogen intermediates generated through the NOSP mediated the suppressive effect was suggested by the reversal of suppression brought about by the addition of a specific inhibitor of the NOSP (NG-monomethyl-l-arginine acetate) to the culture media. No NOSP activity was detectable in LPS-stimulated SC/macrophage cocultures. The role of T cell-derived IFN-gamma in the induction of the NOSP was investigated by the use of anti-IFN-gamma-mAb. Antibody-treated Con A supernatants failed to induce the NOSP in macrophages, and the addition of the mAb to Con A-stimulated SC/macrophage cocultures obviated the suppressive effects. Indomethacin and catalase only partially restored proliferation in Con A-stimulated SC/macrophage cocultures but were remarkably efficient in preventing macrophage-dependent suppression when LPS was used as the mitogenic stimulus. These results demonstrate a regulatory system of potential relevance in sites of predominant macrophage infiltration by which T cell-derived IFN-gamma activates the production of the mediator, NO, that suppresses T cell proliferation. In addition, these data demonstrate that, although the suppressive effects of excess macrophages appear to be expressed nonspecifically toward both T and B cells, suppression is mediated through a different mechanism in each case.
authors.affiliation: Department of Surgery, Rhode Island Hospital, Providence 02903.
authors.forename: J E
authors.initials: JE
authors.lastname: Albina
authors.forename: J A
authors.initials: JA
authors.lastname: Abate
authors.forename: W L
authors.initials: WL
authors.lastname: Henry
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D002374:Catalase / Q000494:pharmacology; D002478:Cells, Cultured; D003208:Concanavalin A / Q000494:pharmacology; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D007371:Interferon-gamma / Q000502:physiology*; D008213:Lymphocyte Activation; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism*; D010529:Peritoneal Cavity / Q000166:cytology; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D003208:Concanavalin A; D009569:Nitric Oxide; D007371:Interferon-gamma; D002374:Catalase; D007213:Indomethacin