title: Pancreatic secretory trypsin inhibitor I reduces the severity of chronic pancreatitis in mice overexpressing interleukin-1β in the pancreas.
abstract: IL-1β is believed to play a pathogenic role in the development of pancreatitis. Expression of human IL-1β 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-1β transgenic [Tg(IL1β)] 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(IL1β) 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(IL1β) mice, pancreatitis was significantly less severe in dual-transgenic [Tg(IL1β)-Tg(Psti1)] mice expressing IL-1β 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.
authors.affiliation: Department of Medicine, Duke University and Durham Veterans Affairs Medical Centers, Durham, North Carolina 27710, USA.
authors.forename: Joelle M-J
authors.initials: JM
authors.lastname: Romac
authors.forename: Rafiq A
authors.initials: RA
authors.lastname: Shahid
authors.forename: Steve S
authors.initials: SS
authors.lastname: Choi
authors.forename: Gamze F
authors.initials: GF
authors.lastname: Karaca
authors.forename: Christoph B
authors.initials: CB
authors.lastname: Westphalen
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Wang
authors.forename: Rodger A
authors.initials: RA
authors.lastname: Liddle
mesh_terms: D000199:Actins / Q000096:biosynthesis; D000681:Amylases / Q000378:metabolism; D000818:Animals; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000502:physiology*; D053583:Interleukin-1beta / Q000096:biosynthesis*; D008297:Male; D051379:Mice; D010179:Pancreas / Q000378:metabolism* / Q000473:pathology; D010195:Pancreatitis / Q000473:pathology; D050500:Pancreatitis, Chronic / Q000473:pathology / Q000517:prevention & control*; D051381:Rats; D014357:Trypsin / Q000378:metabolism; D014359:Trypsin Inhibitor, Kazal Pancreatic; D014361:Trypsin Inhibitors / Q000096:biosynthesis / Q000502:physiology
chemical_list: D000199:Actins; D036341:Intercellular Signaling Peptides and Proteins; D053583:Interleukin-1beta; C504705:Spink1 protein, rat; D014361:Trypsin Inhibitors; C544013:alpha-smooth muscle actin, mouse; D014359:Trypsin Inhibitor, Kazal Pancreatic; D000681:Amylases; D014357:Trypsin