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

Biochem Biophys Res Commun. 2001 Apr 6;282(3):717-22. doi: 10.1006/bbrc.2001.4628.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Base Sequence
  • Cell Line, Transformed
  • Chromans / pharmacology*
  • DNA Primers / genetics
  • Endothelium, Vascular / drug effects*
  • Endothelium, Vascular / metabolism*
  • Enzyme Activation / drug effects
  • Gene Expression / drug effects
  • Genes, fos / drug effects
  • Humans
  • Hypoglycemic Agents / pharmacology
  • Intercellular Adhesion Molecule-1 / genetics*
  • Intercellular Adhesion Molecule-1 / metabolism
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases / metabolism
  • NF-kappa B / metabolism
  • Prostaglandin D2 / analogs & derivatives
  • Prostaglandin D2 / pharmacology
  • Proto-Oncogene Proteins c-fos / genetics
  • Proto-Oncogene Proteins c-fos / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Thiazoles / pharmacology*
  • Thiazolidinediones*
  • Transcription Factor AP-1 / metabolism
  • Transcription Factors / metabolism
  • Troglitazone
  • Tumor Necrosis Factor-alpha / pharmacology


  • 15-deoxy-delta(12,14)-prostaglandin J2
  • Chromans
  • DNA Primers
  • Hypoglycemic Agents
  • NF-kappa B
  • Proto-Oncogene Proteins c-fos
  • RNA, Messenger
  • Receptors, Cytoplasmic and Nuclear
  • Thiazoles
  • Thiazolidinediones
  • Transcription Factor AP-1
  • Transcription Factors
  • Tumor Necrosis Factor-alpha
  • Intercellular Adhesion Molecule-1
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • Troglitazone
  • Prostaglandin D2