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PPAR- knockout in pancreatic epithelial cells abolishes the inhibitory effect of rosiglitazone on caerulein-induced acute pancreatitis

Departments of ¹Molecular and Integrative Physiology, ²Pharmacology, and ³Internal Medicine, Metabolism, Endocrinology, and Diabetes Division, University of Michigan Medical School, Ann Arbor, Michigan

Submitted 31 January 2007 ; accepted in final form 16 April 2007

Peroxisome proliferator-activated receptor- (PPAR-) agonists, such as the thiazolidinediones (TZDs), decrease acute inflammation in both pancreatic cell lines and mouse models of acute pancreatitis. Since PPAR- agonists have been shown to exert some of their actions independent of PPAR-, the role of PPAR- in pancreatic inflammation has not been directly tested. Furthermore, the differential role of PPAR- in endodermal derivatives (acini, ductal cells, and islets) as opposed to the endothelial or inflammatory cells is unknown. To determine whether the effects of a TZD, rosiglitazone, on caerulein-induced acute pancreatitis are dependent on PPAR- in the endodermal derivatives, we created a cell-type specific knock out of PPAR- in pancreatic acini, ducts, and islets. PPAR- knockout animals show a greater response in some inflammatory genes after caerulein challenge. The anti-inflammatory effect of rosiglitazone on edema, macrophage infiltration, and expression of the proinflammatory cytokines is significantly decreased in pancreata of the knockout animals compared with control animals. However, rosiglitazone retains its effect in the lungs of the pancreatic-specific PPAR- knockout animals, likely due to direct anti-inflammatory effect on lung parenchyma. These data show that the PPAR- in the pancreatic epithelia and islets is important in suppressing inflammation and is required for the anti-inflammatory effects of TZDs in acute pancreatitis.

peroxisome proliferator-activated receptor-; caerulein-induced acute pancreatitis; pancreatic epithelial cell-type specific PPAR- knockout; proinflammatory cytokines; rosiglitazone

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