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Dual Function of Troglitazone in ICAM-1 Gene Expression in Human Vascular Endothelium

https://doi.org/10.1006/bbrc.2001.4628Get rights and content

Abstract

Our previous work has shown that troglitazone (an antidiabetic, thiazolidione drug and a synthetic ligand for peroxisome proliferator-activated receptor γ, PPARγ) stimulated basal level of intercellular adhesion molecule-1 (ICAM-1) protein expression in the absence of cytokine stimulation in human vascular endothelial cells. In this study, we examine the molecular mechanism of troglitazone on the basal and TNFα-induced ICAM-1 gene expression. Activation of transcription factors, NF-κB and AP-1 proteins, known to regulate ICAM-1 gene expression upon external stimulators, was examined. In human vascular endothelial cells (ECV304 cells), troglitazone inhibited TNFα-induced ICAM-1 gene expression by suppressing NF-κB/DNA binding activity, NF-κB transcriptional responses, c-Fos mRNA and protein levels via a ligand-dependent, PPARγ-activated manner. In contrast, both troglitazone (at 10 μM) and 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2, at 15 μM), a natural ligand for PPARγ, induce c-Jun phosphorylation by activation of c-Jun N-terminal kinase (JNK) through a posttranslational regulation of c-Jun activity, therefore increasing AP-1/DNA binding activity and transcriptional responses as results of increasing basal ICAM-1 gene expression. These findings suggest dual function of troglitazone in the modulation of both basal and stimulated ICAM-1gene expression in human vascular endothelial cells.

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Abbreviations used: ICAM-1, intercellular adhesion molecule-1; PPARγ, peroxisome proliferator activated receptor γ; nuclear transcription factor κB, NF-κB; AP-1, activating protein-1; JNK, c-Jun N-terminal kinase; TNFα, tumor necrosis factorα; 15d-PGJ2, 15-deoxy-Δ12,14-prostaglandin J2.

1

To whom correspondence should be addressed at City of Hope, Beckman Research Institute, 1500 East Duarte Road, Duarte, CA 91010. Fax: 626-256-6704. E-mail: [email protected].

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