Aim: 

1) To assess the role of serine threonine phosphatases in the up-regulation of pro-inflammatory genes in the pancreas in acute pancreatitis; 2) To investigate the role of serine threonine phosphatases in the mechanism of action of pentoxifylline as a potential therapy in acute pancreatitis.

Design:

Necrotizing pancreatitis was induced in rats by taurocholate. Phosphorylation of ERK and MEK1/2, PP2A, PP2B and PP2C serine threonine phosphatase activities, up-regulation of pro-inflammatory genes (by RT-PCR and chromatin immunoprecipitation) and recruitment of transcription factors and histone acetyltransferases/deacetylases were determined in pancreas in pancreatitis. Taurocholate-treated AR42J acinar cells were also studied.

Results: 

The activities of PP2A, PP2B and PP2C serine threonine phosphatases were reduced by 50%, 57%, and 29%, respectively, in pancreas at 1 h post-induction. The loss in PP2A activity was due to a decrease in cAMP levels. Pentoxifylline as phosphodiesterase inhibitor prevented the loss of PP2A activity induced by taurocholate in vivo and in vitro without affecting the other phosphatases. Pentoxifylline prevented up-regulation of early (egr-1,atf-3) and late (iNOS, ICAM, IL-6, TNF-a) responsive genes as well as recruitment of transcription factors (NF-kB and C/BPb) and histone acetyltransferases to their gene promoters in pancreas in the course of pancreatitis.

Conclusions: 

The loss of phosphatase PP2A activity is a key early event in the inflammatory network in acute pancreatitis. The beneficial effect of pentoxifylline –and presumably of other phosphodiesterase inhibitors- in this disease seems to be mediated by abrogating the loss of cAMP levels and PP2A activity very early in the course of acute pancreatitis.

Supported by Grants SAF2006-06963 and CSD-2007-0020 from M.C.I. to J.S.