P-324 - Time-course of thiol oxidation of protein phosphatases during cerulein-induced acute pancreatitis

Abstract

Acute pancreatitis (AP) is an acute inflammatory process of the pancreatic gland. The aim of this work was to evaluate the role of thiol oxidation of key proteins that can be involved in the regulation of the inflammatory process during AP. AP was induced in C57BL/6 mice by 7 hourly subcutaneous injections of cerulein (50 ug/kg bw). Animals were sacrificed after 1, 3, 5 and 7 injections of cerulein. One hour after the first injection, hyperoxidation of peroxiredoxin 1–4 was detected coinciding with a H2O2 peak. Three hours later, a marked up-regulation of mRNA and protein expression of sulfiredoxin, partially mediated by Nrf-2, takes place. The up-regulation of sulfiredoxin seems to be responsible for the decrease in hyperoxidation of peroxiredoxin 1–4 to allow Prdx1 and Prdx2 reduce H2O2 production in the middle phase of AP induction. During the induction of AP we have detected an overoxidation of protein phosphatases PP2A and SHP2. Inactivation of PP2A and SHP2 during acute pancreatitis by intramolecular disulphide bridges would be favour the early activation of MAPKs JNK, ERK1/2 and p38. Therefore, we conclude that modulation of the redox state of PP2A and SHP2 and peroxiredoxins by sulfiredoxin may play a key role in the up-regulation of the inflammatory cascade.