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. Further, 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 cerulein-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 cerulein challenge. The anti-inflammatory effect of Rosiglitazone on edema, macrophage infiltration and expression of the pro-inflammatory cytokines is significantly decreased in pancreata of the knockout animals when compared to 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.