Inhibition by parthenolide of phorbol ester-induced transcriptional activation of inducible nitric oxide synthase gene in a human monocyte cell line THP-1

Excessive nitric oxide production hy inducible nitric oxide synthase (iNOS) in stimulated inflammatory cells is thought to be a causative factor of ce llular injury in inflammatory disease states. Compounds inhibiting iNOS tra nscriptional activity in inflammatory cells are potentially anti-inflammato ry. An assay method for estimating iNOS transcriptional activity in the hum an monocyte cell line THP-1 was established using a luciferase reporter gen e system. In this study, we demonstrate that parthenolide, the predominant sesquiterpene lactone in European feverfew (Tanacetum parthenium), exerts p otent inhibitory effects on the promoter activity of the iNOS gene in THP-1 cells. Parthenolide effectively suppressed iNOS promoter activity in a dos e-dependent manner at concentrations higher than 2.5 mu M, with an IC50 of about 10 mu M. A tumor-promoting phorbol ester, 12-O-tetradecanoylphorbol-1 3-acetate (TPA), significantly increased the iNOS promoter-dependent report er gene activity, and the TPA-induced increase in iNOS promoter activity wa s effectively suppressed hy parthenolide, with an IC50 of approximately 2 m u M. The present findings may further explain the anti-inflammatory propert y of parthenolide. BIOCHEM PHARMACOL 60;4:595-600, 2000. (C) 2000 Elsevier Science Inc.