We have shown that pretreatment of mice with the peroxisome proliferator-activated receptor-γ agonist, troglitazone ameliorates the severity of cerulein induced acute pancreatitis in vivo as measured by a dose-dependent reduction in serum amylase concentration and improvements in histological scoring of tissue damage. Cerulein caused an 18-fold increase in peak pancreatic tissue TNF-α and 31-fold increase in IL-6 expression 3 hours after the last cerulein injection. Troglitazone pretreatment abolished these increases in cytokine expression. Others have shown cerulein-induced pancreatitis and cytokine expression is mediated by NFκ-B activation. We hypothesized that pretreatment with troglitazone ameliorates the severity of acute pancreatitis by upregulation of IκBα. Acute pancreatitis was induced in C3H mice by cerulein hyperstimulation. Pancreatic tissue-specific expression of IκBα was determined by RT-PCR with expression normalized to acidic ribosomal phosphoprotein (Arbp). Western blots were used to monitor IκBα protein levels. Compared to controls, mice with cerulein pancreatitis had increased normalized pancreatic tissue IκBα mRNA expression 3 hours following the last cerulein injection (3.68 fold increase, p = 0.0007). Western blots showed significant cerulein dependent protein degradation of IκBα at 3 hours (1.88 fold decrease, p = 0.04) consistent with NFκ-B activation. Increased protein turnover was confirmed by the increased phosphorylation of IκBα (2.16 fold, p = 0.022). Normalized IκBα expression in mice pretreated with a single dose of troglitazone prior to induction of cerulein pancreatitis was 5.26 ± 0.69 compared to 1.91 ± 0.43 in controls (p = 0.0001) one hour after the last cerulein or carrier injection. IκBα expression was also increased in mice pretreated with troglitazone in the absence of cerulein induced pancreatitis (4.85 ± 0.55 vs. 2.25 ± 0.29 in control mice, p <0.0001) indicating that troglitazone alone was sufficient for induction. Troglitazone pretreatment completely inhibited the cerulein induced increase in IκBα expression 3 hours after the last injection (1.33 ± 0.14 troglitazone pretreatment vs. 4.42 ± 0.84 cerulein alone, p = 0.0003). These data suggest a mechanism by which troglitazone ameliorates the severity of acute cerulein pancreatitis in vivo by upregulation of the NFκ-B inhibitor, IκBα, resulting in an inhibition of pancreatic tissue inflammatory cytokine release and pancreatic tissue injury.