Dithiolane analogs of lignans inhibit interferon-gamma and lipopolysaccharide-induced nitric oxide production in macrophages

AIM: To investigate the effect of a group of novel synthetic dithiolane ana logs of lignans and a well characterized platelet-activating factor (PAF) r eceptor antagonist, L659,989 on PAF-receptor binding, IFN-gamma- and lipopo lysaccharide (LPS)-induced NO production, and steady-state inducible nitric -oxide synthase (iNOS) mRNA expression. METHODS: PAF-receptor binding study was performed by displacement of H-3-PAF from rabbit platelet membrane; NO production was quantitated by measuring the NO oxidation product, nitrite, in conditioned culture medium; expression of iNOS mRNA was assessed by Nor thern blot analysis. RESULTS: The dithiolane analogs inhibited the producti on of NO,; decreased iNOS mRNA expression and antagonized PAF-receptor bind ing. L659,989 had no effect on NO production and iNOS mRNA expression. Amon g the compounds tested, there was no simple correlation between their PAF-r eceptor antagonistic and iNOS inhibitory activities. CONCLUSION: The dithio lane analogs are a new synthetic chemical class of iNOS expression regulato rs with dual biologic functions: inhibiting iNOS induction and blocking PAF -receptor.