Dithiolane analogs of lignans inhibit interferon-gamma and lipopolysaccharide-induced nitric oxide production in macrophages.
OBJECTIVE
To investigate the effect of a group of novel synthetic dithiolane analogs of lignans and a well characterized platelet-activating factor (PAF) receptor antagonist, L659,989 on PAF-receptor binding, IFN-gamma- and lipopolysaccharide (LPS)-induced NO production, and steady-state inducible nitric-oxide synthase (iNOS) mRNA expression.


METHODS
PAF-receptor binding study was performed by displacement of 3H-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 Northern blot analysis.


RESULTS
The dithiolane analogs inhibited the production of NO, decreased iNOS mRNA expression and antagonized PAF-receptor binding. L659,989 had no effect on NO production and iNOS mRNA expression. Among the compounds tested, there was no simple correlation between their PAF-receptor antagonistic and iNOS inhibitory activities.


CONCLUSIONS
The dithiolane analogs are a new synthetic chemical class of iNOS expression regulators with dual biologic functions: inhibiting iNOS induction and blocking PAF-receptor.
Hussaini
I M
IM
Department of Pathology, University of Virginia, Charlottesville, VA 22908, USA. imh5c@virginia.edu
Zhang
Y H
YH
Lysiak
J J
JJ
Shen
T Y
TY
D000818:Animals; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors; D017705:Lignans / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis* / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D011994:Recombinant Proteins
D006571:Heterocyclic Compounds; D017705:Lignans; D008070:Lipopolysaccharides; D010980:Platelet Membrane Glycoproteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D011994:Recombinant Proteins; C039351:platelet activating factor receptor; D009569:Nitric Oxide; C012948:1,3-dithiolane; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse