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

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.

• Authors: F Marra, E Efsen, R G Romanelli, A Caligiuri, S Pastacaldi, G Batignani, A Bonacchi, R Caporale, G Laffi, M Pinzani, P Gentilini
• Journal: Gastroenterology (Gastroenterology) Vol. 119 Issue 2 Pg. 466-78 (Aug 2000) ISSN: 0016-5085 [Print] United States
• PMID: 10930382 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• Antineoplastic Agents (pharmacology)
• Biological Transport (drug effects, immunology)
• Cell Division (immunology)
• Cell Movement (immunology)
• Cell Survival (drug effects)
• Cells, Cultured
• Chemokine CCL2 (genetics, metabolism)
• Chromans (pharmacology)
• Cytotoxins (metabolism)
• Gene Expression (immunology)
• Hepatitis (immunology, metabolism, pathology)
• Humans
• Interleukin-1 (pharmacology)
• Ligands
• Liver (cytology, immunology, metabolism)
• Liver Cirrhosis (immunology, metabolism, pathology)
• Mitogen-Activated Protein Kinases (metabolism)
• NF-kappa B (metabolism)
• Phosphorylation
• Platelet-Derived Growth Factor (metabolism)
• Prostaglandin D2 (analogs & derivatives, 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