title: Conjugated polyhydroxybenzene derivatives block tumor necrosis factor-alpha-mediated nuclear factor-kappaB activation and cyclooxygenase-2 gene transcription by targeting IkappaB kinase activity.
abstract: Because the transcription factor, nuclear factor (NF)-kappaB, plays a key role in cellular inflammatory and immune responses, components of the NF-kappaB-activating signaling pathways are frequently used as targets for anti-inflammatory agents. This study shows that 2-(3',4'-dihydroxyphenyl)-5-hydroxybenzo[b]furan (GF-015) and 2,3-di(3',4'-dihydroxy-transstyryl) pyridine (GF-90), two conjugated polyhydroxybenzene derivatives, inhibited a common step in NF-kappaB activation in human NCI-H292 epithelial cells by preventing tumor necrosis factor (TNF)-alpha- and 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced IkappaB kinase (IKK) complex activation. Both agents inhibited the TNF-alpha- or TPA-induced expression of cyclooxygenase (COX)-2 mRNA and protein, COX-2 promoter activity, and prostaglandin E2 (PGE2) production. Overexpression of wild-type NF-kappaB-inducing kinase, IKKalpha, and IKKbeta led, respectively, to 3.5-, 2.6-, and 2.6-fold increases in COX-2 promoter activity, and these effects were inhibited by both compounds. GF-015 and GF-90 also prevented the TNF-alpha- and TPA-induced activation of IKK and NF-kappaB-specific DNA-protein binding activity. These results suggest that the inhibitory effect of GF-015 and GF-90 on TNF-alpha-induced COX-2 protein expression was caused by suppression of IKK activity and NF-kappaB activation in the COX-2 promoter, resulting in attenuation of COX-2 gene expression and PGE2 production.
authors.affiliation: Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan. ccchen@ha.mc.ntu.edu.tw
authors.forename: C C
authors.initials: CC
authors.lastname: Chen
authors.forename: K T
authors.initials: KT
authors.lastname: Chiu
authors.forename: S T
authors.initials: ST
authors.lastname: Chan
authors.forename: J W
authors.initials: JW
authors.lastname: Chern
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001572:Benzofurans / Q000494:pharmacology*; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins; D007527:Isoenzymes / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000502:physiology*
chemical_list: C441523:2,3-di(3',4'-dihydroxy-transstyryl) pyridine; C441522:2-(3',4'-dihydroxyphenyl)-5-hydroxybenzo(b)furan; D000893:Anti-Inflammatory Agents; D001572:Benzofurans; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D007527:Isoenzymes; D008565:Membrane Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D011725:Pyridines; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D004247:DNA; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; D015232:Dinoprostone; D013755:Tetradecanoylphorbol Acetate