Dual function of troglitazone in ICAM-1 gene expression in human vascular endothelium.
Our previous work has shown that troglitazone (an antidiabetic, thiazolidione drug and a synthetic ligand for peroxisome proliferator-activated receptor gamma, PPARgamma) 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 TNFalpha-induced ICAM-1 gene expression. Activation of transcription factors, NF-kappaB 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 TNFalpha-induced ICAM-1 gene expression by suppressing NF-kappaB/DNA binding activity, NF-kappaB transcriptional responses, c-Fos mRNA and protein levels via a ligand-dependent, PPARgamma-activated manner. In contrast, both troglitazone (at 10 microM) and 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2), at 15 microM), a natural ligand for PPARgamma, 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.
Chen
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Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA. nchen@coh.org
Han
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D001483:Base Sequence; D002461:Cell Line, Transformed; D002839:Chromans / Q000494:pharmacology*; D017931:DNA Primers / Q000235:genetics; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D016762:Genes, fos / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics* / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D000077288:Troglitazone; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D002839:Chromans; D017931:DNA Primers; D007004:Hypoglycemic Agents; D016328:NF-kappa B; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D000077288:Troglitazone; D015230:Prostaglandin D2