Vol. 60, Issue 6, 1439-1448, December 2001

Conjugated Polyhydroxybenzene Derivatives Block Tumor Necrosis Factor--Mediated Nuclear Factor-B Activation and Cyclooxygenase-2 Gene Transcription by Targeting IB Kinase Activity

Ching-Chow Chen, Kuo-Tung Chiu, Shu-Ting Chan, and Ji-Wang Chern

Department of Pharmacology (C.-C.C., K.-T.C., S.-T.C.) and School of Pharmacy (J.-W.C.), College of Medicine, National Taiwan University, Taipei, Taiwan

Because the transcription factor, nuclear factor (NF)-B, plays a key role in cellular inflammatory and immune responses, components of the NF-B-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-B activation in human NCI-H292 epithelial cells by preventing tumor necrosis factor (TNF)-- and 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced IB kinase (IKK) complex activation. Both agents inhibited the TNF-- 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-B-inducing kinase, IKK, and IKK 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-- and TPA-induced activation of IKK and NF-B-specific DNA-protein binding activity. These results suggest that the inhibitory effect of GF-015 and GF-90 on TNF--induced COX-2 protein expression was caused by suppression of IKK activity and NF-B activation in the COX-2 promoter, resulting in attenuation of COX-2 gene expression and PGE₂ production.