The natural product hymenialdisine inhibits interleukin-8 production in U937 cells by inhibition of nuclear factor-kappaB.
The nuclear factor-kappaB (NF-kappaB) 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-kappaB would be a useful therapeutic agent in a variety of inflammatory disorders. The marine natural product hymenialdisine was evaluated as an inhibitor of NF-kappaB 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-kappaB. Hymenialdisine caused a concentration-dependent decrease in luciferase production from both reporters when the cells were stimulated with tumor necrosis factor-alpha, lipopolysaccharide or phorbol myristate acetate. An electrophoretic mobility shift assay confirmed its activity by inhibiting DNA binding of NF-kappaB. Hymenialdisine was shown to be a selective inhibitor of NF-kappaB 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-alpha-stimulated luciferase and IL-8 production. The compound also had no effect on IkappaB alpha or IkappaB beta phosphorylation and degradation. Thus, hymenialdisine is a potent inhibitor of NF-kappaB and IL-8 production in U937 cells.
Breton
J J
JJ
Department of Immunopharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406-0939, USA.
Chabot-Fletcher
M C
MC
D001381:Azepines / Q000494:pharmacology*; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000235:genetics; D008156:Luciferases / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D051841:Transcription Factor RelB; D014157:Transcription Factors; D014407:Tumor Cells, Cultured
D001381:Azepines; D016209:Interleukin-8; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D011758:Pyrroles; C497593:RELB protein, human; D012333:RNA, Messenger; D014157:Transcription Factors; D051841:Transcription Factor RelB; C107079:hymenialdisine; D008156:Luciferases