Dual function of troglitazone in ICAM-1 gene expression in human vascular endothelium

Our previous work has shown that troglitazone (an antidiabetic, thiazolidio ne drug and a synthetic ligand for peroxisome proliferator-activated recept or gamma, PPAR gamma) stimulated basal level of intercellular adhesion mole cule-1 (ICAM-1) protein expression in the absence of cytokine stimulation i n human vascular endothelial cells. In this study, we examine the molecular mechanism of troglitazone on the basal and TNF alpha -induced ICAM-1 gene expression. Activation of transcription factors, NF-KB and AP-1 proteins, k nown to regulate ICAM-1 gene expression upon external stimulators, was exam ined. In human vascular endothelial cells (ECV304 cells), troglitazone inhi bited TNF alpha -induced ICAM-1 gene expression by suppressing NF-kappaB/DN A binding activity, NF-KB transcriptional responses, c-Fos mRNA and protein levels via a ligand-dependent, PPAR gamma -activated manner. In contrast, both troglitazone (at 10 muM) and 15-deoxy-Delta (12,14)-prostaglandin J(2) (15d-PGJ(2), at 15 muM), a natural ligand for PPAR gamma, induce c-Jun pho sphorylation by activation of c-Jun N-terminal kinase (JNK) through a postt ranslational regulation of c-Tun activity, therefore increasing AP-1/DNA bi nding activity and transcriptional responses as results of increasing basal ICAM-1 gene expression. These findings suggest dual function of troglitazo ne in the modulation of both basal and stimulated ICAM-1 gene expression in human vascular endothelial cells. (C) 2001 Academic Press.