Ligands of peroxisome proliferator-activated receptor gamma modulate profibrogenic and proinflammatory actions in hepatic stellate cells

Gastroenterology. 2000 Aug;119(2):466-78. doi: 10.1053/gast.2000.9365.

Abstract

Background & aims: Proliferation and migration of hepatic stellate cells (HSCs) and expression of chemokines are involved in the pathogenesis of liver inflammation and fibrogenesis. Peroxisome proliferator-activated receptor (PPAR)-gamma is a receptor transcription factor that controls growth and differentiation in different tissues. We explored the effects of PPAR-gamma agonists on the biological actions of cultured human HSCs.

Methods: HSCs were isolated from normal human liver tissue and used in their myofibroblast-like phenotype or immediately after isolation. Activation of PPAR-gamma was induced with 15-deoxy-Delta(12, 14)-prostaglandin J(2) or with troglitazone.

Results: PPAR-gamma agonists dose-dependently inhibited HSC proliferation and chemotaxis induced by platelet-derived growth factor. This effect was independent of changes in postreceptor signaling or expression of c-fos and c-myc and was associated with inhibition of cell cycle progression beyond the G(1) phase. Activation of PPAR-gamma also resulted in a complete inhibition of the expression of monocyte chemotactic protein 1 at the gene and protein levels. Comparison of quiescent and culture-activated HSCs revealed a marked decrease in PPAR-gamma expression in activated cells.

Conclusions: Activation of PPAR-gamma modulates profibrogenic and proinflammatory actions in HSCs. Reduced PPAR-gamma expression may contribute to confer an activated phenotype to HSCs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Biological Transport / drug effects
  • Biological Transport / immunology
  • Cell Division / immunology
  • Cell Movement / immunology
  • Cell Survival / drug effects
  • Cells, Cultured
  • Chemokine CCL2 / genetics
  • Chemokine CCL2 / metabolism
  • Chromans / pharmacology
  • Cytotoxins / metabolism
  • Gene Expression / immunology
  • Hepatitis / immunology
  • Hepatitis / metabolism*
  • Hepatitis / pathology
  • Humans
  • Interleukin-1 / pharmacology
  • Ligands
  • Liver / cytology*
  • Liver / immunology*
  • Liver / metabolism
  • Liver Cirrhosis / immunology
  • Liver Cirrhosis / metabolism*
  • Liver Cirrhosis / pathology
  • Mitogen-Activated Protein Kinases / metabolism
  • NF-kappa B / metabolism
  • Phosphorylation
  • Platelet-Derived Growth Factor / metabolism
  • Prostaglandin D2 / analogs & derivatives
  • Prostaglandin D2 / pharmacology
  • Proto-Oncogenes / genetics
  • RNA, Messenger / analysis
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Thiazoles / pharmacology
  • Thiazolidinediones*
  • Transcription Factor AP-1 / metabolism
  • Transcription Factors / metabolism*
  • Troglitazone
  • Tyrosine / metabolism
  • Wound Healing / immunology
  • p38 Mitogen-Activated Protein Kinases

Substances

  • 15-deoxy-delta(12,14)-prostaglandin J2
  • Antineoplastic Agents
  • Chemokine CCL2
  • Chromans
  • Cytotoxins
  • Interleukin-1
  • Ligands
  • NF-kappa B
  • Platelet-Derived Growth Factor
  • RNA, Messenger
  • Receptors, Cytoplasmic and Nuclear
  • Thiazoles
  • Thiazolidinediones
  • Transcription Factor AP-1
  • Transcription Factors
  • Tyrosine
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Troglitazone
  • Prostaglandin D2