Ligands of peroxisome proliferator-activated receptor-γ 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-Delta (12,14) -prostaglandin J(2) (15d-PGJ(2)) 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 G(1) phase. PPAR-gamma ligands decreased a-smooth muscle actin protein expression and alpha1(1) 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-PGJ(2), but not troglitazone, inhibited the degradation of IKB-alpha and consequent NF-B-K activation. In conclusion, activation of PPAR-y inhibited profibrogenic and proinflammatory actions in activated PSCs, suggesting a potential application of PPAR-y ligands in the treatment of pancreatic fibrosis and inflammation.