Pancreatic secretory trypsin inhibitor I reduces the severity of chronic pancreatitis in mice overexpressing interleukin-1β in the pancreas

Romac JM, Shahid RA, Choi SS, Karaca GF, Westphalen CB, Wang TC, Liddle RA. Pancreatic secretory trypsin inhibitor I reduces the severity of chronic pancreatitis in mice overexpressing interleukin-1 beta in the pancreas. Am J Physiol Gastrointest Liver Physiol 302: G535-G541, 2012. First published December 15, 2011; doi:10.1152/ajpgi.00287.2011.-IL-1 beta is believed to play a pathogenic role in the development of pancreatitis. Expression of human IL-1 beta in pancreatic acinar cells produces chronic pancreatitis, characterized by extensive intrapancreatic inflammation, atrophy, and fibrosis. To determine if activation of trypsinogen is important in the pathogenesis of chronic pancreatitis in this model, we crossed IL-1 beta transgenic [Tg(IL1 beta)] mice with mice expressing a trypsin inhibitor that is normally produced in rat pancreatic acinar cells [pancreatic secretory trypsin inhibitor (PTSI) I]. We previously demonstrated that transgenic expression of PSTI-I [Tg(Psti1)] increased pancreatic trypsin inhibitor activity by 190%. Tg(IL1 beta) mice were found to have marked pancreatic inflammation, characterized by histological changes, including acinar cell loss, inflammatory cell infiltration, and fibrosis, as well as elevated myeloperoxidase activity and elevated pancreatic trypsin activity, as early as 6 wk of age. In contrast to Tg(IL1 beta) mice, pancreatitis was significantly less severe in dual-transgenic [Tg(IL1 beta)-Tg(Psti1)] mice expressing IL-1 beta and PSTI-I in pancreatic acinar cells. These findings indicate that overexpression of PSTI-I reduces the severity of pancreatitis and that pancreatic trypsin activity contributes to the pathogenesis of an inflammatory model of chronic pancreatitis.