Ligands of peroxisome proliferator-activated receptor-gamma block activation of pancreatic stellate cells.
Activated pancreatic stellate cells (PSCs) have recently been implicated in the pathogenesis of pancreatic fibrosis and inflammation. Peroxisome proliferator-activated receptor gamma (PPAR-gamma) is a ligand-activated transcription factor which controls growth, differentiation, and inflammation in different tissues. Roles of PPAR-gamma activation in PSCs are poorly characterized. Here we examined the effects of PPAR-gamma ligands on the key parameters of PSC activation. PSCs were isolated from rat pancreas tissue, and used in their culture-activated, myofibroblast-like phenotype. Activation of PPAR-gamma was induced with 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) or with troglitazone. Expression of PPAR-gamma was predominantly localized in the nuclei, and PPAR-gamma was transcriptionally active after ligand stimulation. PPAR-gamma ligands inhibited platelet-derived growth factor-induced proliferation. This effect was associated with inhibition of cell cycle progression beyond the G1 phase. PPAR-gamma ligands decreased alpha-smooth muscle actin protein expression and alpha1(I) procollagen and prolyl 4-hydroxylase(alpha) mRNA levels. Activation of PPAR-gamma also resulted in the inhibition of inducible monocyte chemoattractant protein-1 expression. 15d-PGJ2, but not troglitazone, inhibited the degradation of IkappaB-alpha and consequent NF-kappaB activation. In conclusion, activation of PPAR-gamma inhibited profibrogenic and proinflammatory actions in activated PSCs, suggesting a potential application of PPAR-gamma ligands in the treatment of pancreatic fibrosis and inflammation.
Masamune
Atsushi
A
Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan. amasamune@int3.med.tohoku.ac.jp
Kikuta
Kazuhiro
K
Satoh
Masahiro
M
Sakai
Yoshitaka
Y
Satoh
Akihiko
A
Shimosegawa
Tooru
T
D000199:Actins / Q000032:analysis; D000818:Animals; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000032:analysis; D002839:Chromans / Q000494:pharmacology*; D024042:Collagen Type I / Q000032:analysis; D016193:G1 Phase; D008024:Ligands; D016328:NF-kappa B / Q000378:metabolism; D010179:Pancreas / Q000737:chemistry / Q000166:cytology* / Q000187:drug effects; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000502:physiology*; D000077288:Troglitazone
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D000199:Actins; D018932:Chemokine CCL2; D002839:Chromans; D024042:Collagen Type I; D008024:Ligands; D016328:NF-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077288:Troglitazone; D015230:Prostaglandin D2