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