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