title: Cyclic guanosine 3',5'-monophosphate mediates 3-morpholinosydnonimine-induced inhibition of human natural killer cells.
abstract: Nitric oxide (NO) donors were used to investigate the effect of NO on and the role of cyclic GMP in the regulation of human natural killer (NK) cell function. NO-producing drugs, molsidomine and its metabolite 3-morpholinesydnonimine (SIN-1), inhibited NK cell-mediated cytotoxicity significantly at 0.04-5 mM. At 1 mM, SIN-1 completely inhibited NK cell activity while molsidomine decreased NK cell-mediated cytolysis by 35% of the control value. These data suggest that NO from exogenous NO-donors may down-regulate NK cell cytotoxic function. The stimulatory effect of interferon-gamma (IFN-gamma) on human NK cell-mediated killing could not overtake the NK cell inhibition induced by the NO releasing drugs, indicating different modes of action for IFN-gamma and SIN-1. The results in the present study also showed that SIN-1 (1 mM) stimulated cyclic GMP production 37-fold in NK cells. In the presence of 0.5 mM IBMX, a phosphodiesterase inhibitor, the increase in cyclic GMP was even more pronounced, demonstrating a relation between cyclic GMP stimulation and NK cell inhibition by SIN-1. Further evidence for mediation via cyclic GMP was provided by the finding that methylene blue (20 microM), an inhibitor of soluble guanylate cyclase, decreased both the inhibition of SIN-1-induced NK cell cytotoxicity as well as cyclic GMP formation. Moreover, membrane-penetrating cyclic GMP and its analogues inhibited NK cell-mediated cytolysis significantly. Molsidomine was without effect on cyclic GMP levels. Our data indicate that cyclic GMP may play a role in human NK cell regulation and suggest that the inhibitory effect of cGMP may be elicited by NO.
authors.affiliation: Clinical Research Centre, Novum, Huddinge Hospital, Karolinska Institute, Stockholm, Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Xiao
authors.forename: C G
authors.initials: CG
authors.lastname: Nilsson
authors.forename: P H
authors.initials: PH
authors.lastname: Eneroth
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000328:Adult; D006152:Cyclic GMP / Q000378:metabolism*; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000187:drug effects*; D008751:Methylene Blue / Q000494:pharmacology; D008981:Molsidomine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D009569:Nitric Oxide; C002385:linsidomine; D007371:Interferon-gamma; D008981:Molsidomine; D006152:Cyclic GMP; D008751:Methylene Blue; D015056:1-Methyl-3-isobutylxanthine