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HORMONES AND SIGNALING

Protease activation during in vivo pancreatitis is dependent on calcineurin activation

Departments of ¹Pediatrics and ²Pathology, Yale University School of Medicine, New Haven, Connecticut

Submitted May 14, 2009 ; accepted in final form August 20, 2009

The premature activation of digestive proenzymes, specifically proteases, within the pancreatic acinar cell is an early and critical event during acute pancreatitis. Our previous studies demonstrate that this activation requires a distinct pathological rise in cytosolic Ca²⁺. Furthermore, we have shown that a target of aberrant Ca²⁺ in acinar cells is the Ca²⁺/calmodulin-dependent phosphatase calcineurin (PP2B). In this study, we hypothesized that PP2B mediates in vivo protease activation and pancreatitis severity. To test this, pancreatitis was induced in mice over 8 h by administering hourly intraperitoneal injections of the cholecystokinin analog caerulein (50 µg/kg). Treatment with the PP2B inhibitor FK506 at 1 and 8 h after pancreatitis induction reduced trypsin activities by greater than 50% (P < 0.005). Serum amylase and IL-6 was reduced by 86 and 84% relative to baseline (P < 0.0005) at 8 h, respectively. Histological severity of pancreatitis, graded on the basis of pancreatic edema, acinar cell vacuolization, inflammation, and apoptosis, was reduced early in the course of pancreatitis. Myeloperoxidase activity from both pancreas and lung was reduced by 93 and 83% relative to baseline, respectively (P < 0.05). These data suggest that PP2B is an important target of the aberrant acinar cell Ca²⁺ rise associated with pathological protease activation and pancreatitis.

acinar cell; tacrolimus; zymogen activation; calcium signaling; protein phosphatase 2B