SOME ANTIOXIDANTS INHIBIT, IN A COORDINATE FASHION, THE PRODUCTION OFTUMOR-NECROSIS-FACTOR-ALPHA, IL-BETA, AND IL-6 BY HUMAN PERIPHERAL-BLOOD MONONUCLEAR-CELLS

Some antioxidants, including butylated hydroxyanisole (BHA), tetrahydr opapaveroline (THP), nordihydroguiauretic acid, and 10,11-dihydroxyapo rphine (DHA), were found to be potent inhibitors of the production of tumor necrosis factor (TNF)-alpha, IL-1beta, and IL-6 by human periphe ral blood mononuclear cells (PBMC) stimulated by lipopolysaccharide (L PS) (IC50S in the low micromolar range). Inhibition of cytokine produc tion was gene selective and not due to general effects on protein synt hesis. Inhibition of cytokine production by PBMC was observed also whe n other inducers were used (staphylococci, silica, zymosan). Much high er concentrations of other antioxidants-including ascorbic acid, trolo x, alpha-tocopherol, butylated hydroxytoluene, and the 5-lipoxygenase inhibitor zileuton-did not affect the production of these cytokines. T he active compounds did not inhibit IL-1-induced production of IL-6 in fibroblasts, showing the cell selectivity of the effect. Antioxidant- mediated inhibition of cytokine production was correlated with low lev els of the corresponding messenger RNAs. Nuclear run-on experiments sh owed that THP inhibited transcription of the IL-1beta gene. THP decrea sed the concentration of the transcription factors NF-chiB and AP-1 de tected in nuclear extracts of PBMC cultured in the presence or absence of LPS. THP and DHA markedly decreased the levels of TNF-alpha and IL -1beta in the circulation of mice following LPS injection. Thus antiox idants vary widely in potency as inhibitors of the activation of trans cription factors and of the transcription of genes for pro-inflammator y cytokines. Coordinate inhibition of the transcription of genes for i nflammatory cytokines could provide a strategy for therapy of diseases with inflammatory pathogenesis and for septic shock.