Peroxisome proliferator-activated receptor  ligand prevents the development of chronic pancreatitis through modulating NF-B-dependent proinflammatory cytokine production and pancreatic stellate cell activation

Hisada S, Shimizu K, Shiratori K, Kobayashi M

Abstract

Purpose: Thiazolidinedione derivatives (TZDs) are known to be ligands of peroxisome proliferator-activated receptor  (PPAR). In this study, we investigated the effect of a TZD, troglitazone, on inflammation and fibrogenesis in the pancreas of an experimental model of chronic pancreatitis.
Material and methods: Male WBN/Kob rats with spontaneous chronic pancreatitis were fed rat chow containing 0.2% troglitazone from 1 to 4 months of age. Immunohistochemical studies of rat pancreas were carried out with monoclonal mouse antibody against human alpha-smooth muscle actin (-SMA) or rabbit polyclonal antibody against collagen type I, collagen type III, or fibronectin. Cytokine production was measured by enzyme-linked immunosor­bent assay. The inhibitory action of troglitazone on nuclear factor-B (NF-B) binding activity in activated macrophages was also investigated.
Results: Long-term administration of troglitazone reduced inflammatory cell infiltration and fibrosis in the pancreas of WBN/Kob rats, and expression of -SMA, procollagen I, III, and fibronectin was significantly reduced by troglitazone. The increase in TNF- production by activated macrophages was significantly decreased by troglitazone. Peritoneal macrophages isolated from WBN/Kob rats produced a large amount of TNF-, whereas those from troglitazone-treated WBN/Kob rats produced only a marginal amount of TNF-. Lipopolysaccharide-induced NF-B binding activity in peritoneal macrophages was also significantly reduced by troglitazone.
Conclusions: Troglitazone prevented the progression of chronic pancreatitis via inhibition of ECM synthesis and proinflammatory cytokine production mediated by the inhibition of NF-B activity.

Key words: 	thiazolidinedione derivatives, chronic pancreatitis, PPAR, TNF-, NF-B.