TY - JOUR T1 - The Natural Product Hymenialdisine Inhibits Interleukin-8 Production in U937 Cells by Inhibition of Nuclear Factor-κB JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 459 LP - 466 VL - 282 IS - 1 AU - John J. Breton AU - Marie C. Chabot-Fletcher Y1 - 1997/07/01 UR - http://jpet.aspetjournals.org/content/282/1/459.abstract N2 - The nuclear factor-κB (NF-κB) family of transcription factors have been implicated in the inducible expression of genes involved in inflammatory and immune responses. As such, a specific inhibitor of NF-κB would be a useful therapeutic agent in a variety of inflammatory disorders. The marine natural product hymenialdisine was evaluated as an inhibitor of NF-κB in U937 cells. U937 cells were transfected with either a luciferase reporter plasmid containing the human immunodeficiency virus long terminal repeat or the interleukin-8 (IL-8) core promoter, both of which are activated by NF-κB. Hymenialdisine caused a concentration-dependent decrease in luciferase production from both reporters when the cells were stimulated with tumor necrosis factor-α, lipopolysaccharide or phorbol myristate acetate. An electrophoretic mobility shift assay confirmed its activity by inhibiting DNA binding of NF-κB. Hymenialdisine was shown to be a selective inhibitor of NF-κB in that it had no effect on the binding of other transcription factors to their DNA concensus motifs; these included activator protein-1, CCAAT/enhancer binding protein and Sp1. Functional studies showed hymenialdisine to be an inhibitor of IL-8 production and IL-8 mRNA formation in the U937 cell. Investigation into the mechanism of action of hymenialdisine showed that it was not due to inhibition of protein kinase C because the selective protein kinase C inhibitor RO 32–0432 was inactive against tumor necrosis factor-α-stimulated luciferase and IL-8 production. The compound also had no effect on IκBα or IκBβ phosphorylation and degradation. Thus, hymenialdisine is a potent inhibitor of NF-κB and IL-8 production in U937 cells. The American Society for Pharmacology and Experimental Therapeutics ER -