Peroxisome proliferator-activated receptor gamma ligand prevents the development of chronic pancreatitis through modulating NF-kappaB-dependent proinflammatory cytokine production and pancreatic stellate cell activation.
OBJECTIVE
Thiazolidinedione derivatives (TZDs) are known to be ligands of peroxisome proliferator-activated receptor gamma (PPARgamma). 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.


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 (alpha-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-kappaB (NF-kappaB) 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 alpha-SMA, procollagen I, III, and fibronectin was significantly reduced by troglitazone. The increase in TNF-alpha production by activated macrophages was significantly decreased by troglitazone. Peritoneal macrophages isolated from WBN/Kob rats produced a large amount of TNF-alpha, whereas those from troglitazone-treated WBN/Kob rats produced only a marginal amount of TNF-alpha. Lipopolysaccharide-induced NF-kappaB 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-kappaB activity.
Hisada
S
S
Department of Gastroenterology and Pathology, Tokyo Women's Medical University, School of Medicine, Japan.
Shimizu
K
K
Shiratori
K
K
Kobayashi
M
M
D000199:Actins / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002839:Chromans / Q000627:therapeutic use*; D002908:Chronic Disease; D024042:Collagen Type I / Q000378:metabolism; D024061:Collagen Type III / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005353:Fibronectins / Q000378:metabolism; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000378:metabolism; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism*; D010195:Pancreatitis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051381:Rats; D011919:Rats, Inbred Strains; D017208:Rats, Wistar; D045162:Thiazolidinediones / Q000627:therapeutic use*; D000077288:Troglitazone; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D000199:Actins; D000970:Antineoplastic Agents; D002839:Chromans; D024042:Collagen Type I; D024061:Collagen Type III; D005353:Fibronectins; D008024:Ligands; D008070:Lipopolysaccharides; D016328:NF-kappa B; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077288:Troglitazone; D014409:Tumor Necrosis Factor-alpha; C498862:Acta2 protein, rat