Troglitazone inhibits the progression of chronic pancreatitis and the profibrogenic activity of pancreatic stellate cells via a PPARgamma-independent mechanism.
We have previously reported that troglitazone inhibits proinflammatory cytokine production in chronic pancreatitis. In the present study, we show that troglitazone prevents the progression of chronic pancreatitis by inhibiting the proliferation of pancreatic stellate cells (PSCs) via a PPARgamma-independent mechanism. WBN/Kob rats with spontaneous chronic pancreatitis were fed troglitazone-containing rat chow for 3 or 6 months. Pancreatic fibrosis and expression of alpha-SMA were markedly attenuated by troglitazone. Rat PSCs expressed a higher level of PPARgamma1 mRNA than of PPARgamma2 mRNA. PSCs were transiently cotransfected with a dominant negative mutant PPARgamma1 and a PPAR-driven reporter gene. Troglitazone increased reporter activity and the mutant receptor abrogated wild-type receptor activity in a dose-dependent manner. Troglitazone inhibited cell proliferation by blocking cell-cycle progression beyond the G1 phase. These effects were observed in mutant receptor-transfected cells as well as cells transfected with the control vector. The effect of troglitazone on alpha1(I) procollagen mRNA and MCP-1 mRNA was unaffected by inhibition of endogenous PPARgamma1 receptor activity. These results suggest that troglitazone may serve as novel therapeutic agent for the treatment of chronic pancreatitis. The antifibrotic effect of troglitazone appears to be mediated, in part, via a PPARgamma-independent mechanism.
Shimizu
Kyoko
K
Department of Clinical Laboratory, School of Medicine, Tokyo Women's Medical University, Tokyo, Japan. kyoko@ige.twmu.ac.jp
Shiratori
Keiko
K
Kobayashi
Makio
M
Kawamata
Hitoshi
H
D000199:Actins / Q000096:biosynthesis; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured / Q000166:cytology / Q000187:drug effects; D002839:Chromans / Q000494:pharmacology* / Q000627:therapeutic use; D002908:Chronic Disease; D018450:Disease Progression; D004353:Drug Evaluation, Preclinical; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis; D005355:Fibrosis; D016193:G1 Phase / Q000187:drug effects; D017930:Genes, Reporter; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D010179:Pancreas / Q000166:cytology; D010195:Pancreatitis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051381:Rats; D011922:Rats, Mutant Strains; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects; D045162:Thiazolidinediones / Q000494:pharmacology* / Q000627:therapeutic use; D014157:Transcription Factors / Q000187:drug effects; D014162:Transfection; D000077288:Troglitazone
D000199:Actins; D002839:Chromans; D016326:Extracellular Matrix Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D045162:Thiazolidinediones; D014157:Transcription Factors; D008156:Luciferases; D000077288:Troglitazone