Ligands of peroxisome proliferator-activated receptor gamma modulate profibrogenic and proinflammatory actions in hepatic stellate cells.
OBJECTIVE
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.
Dipartimento di Medicina Interna, Università di Firenze, Florence, Italy. f.marra@dfc.unifi.it
F
F
Marra
E
E
Efsen
R G
RG
Romanelli
A
A
Caligiuri
S
S
Pastacaldi
G
G
Batignani
A
A
Bonacchi
R
R
Caporale
G
G
Laffi
M
M
Pinzani
P
P
Gentilini
D000970:Antineoplastic Agents / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D002839:Chromans / Q000494:pharmacology; D003603:Cytotoxins / Q000378:metabolism; D015870:Gene Expression / Q000276:immunology; D006505:Hepatitis / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D008024:Ligands; D008099:Liver / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D008103:Liver Cirrhosis / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D011519:Proto-Oncogenes / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; 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; D014443:Tyrosine / Q000378:metabolism; D014945:Wound Healing / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D000970:Antineoplastic Agents; D018932:Chemokine CCL2; D002839:Chromans; D003603:Cytotoxins; D007375:Interleukin-1; D008024:Ligands; D016328:NF-kappa B; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D014443:Tyrosine; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000077288:Troglitazone; D015230:Prostaglandin D2