Dopamine D2 receptor signalling controls inflammation in acute pancreatitis via a PP2A-dependent Akt/NF-κB signalling pathway.

BACKGROUND AND
PURPOSE: Dopamine has multiple anti-inflammatory effects, but its role and molecular mechanism in acute pancreatitis (AP) are unclear. We investigated the role of dopamine signalling in the inflammatory response in AP. EXPERIMENTAL APPROACH: Changes in pancreatic dopaminergic system and effects of dopamine, antagonists and agonists of D1 and D2 dopamine receptors were analysed in wild-type and pancreas-specific Drd2-/- mice with AP (induced by caerulein and LPS or L-arginine) and pancreatic acinar cells with or without cholecystokinin (CCK) stimulation. The severity of pancreatitis was assessed by measuring serum amylase and lipase and histological assessments. The NF-κB signalling pathway was evaluated, and macrophage and neutrophil migration assessed by Transwell assay. KEY
RESULTS: Pancreatic dopamine synthetase and metabolic enzyme levels were increased, whereas D1 and D2 receptors were decreased in AP. Dopamine reduced inflammation in CCK-stimulated pancreatic acinar cells by inhibiting the NF-κB pathway. Moreover, the protective effects of dopamine were blocked by a D2 antagonist, but not a D1 antagonist. A D2 agonist reduced pancreatic damage and levels of p-IκBα, p-NF-κBp65, TNFα, IL-1β and IL-6 in AP. Pancreas-specific Drd2-/- aggravated AP. Also, the D2 agonist activated PP2A and inhibited the phosphorylation of Akt, IKK, IκBα and NF-κB and production of inflammatory cytokines and chemokines. Furthermore, it inhibited the migration of macrophages and neutrophils by reducing the expression of CCL2 and CXCL2. A PP2A inhibitor attenuated these protective effects of the D2 agonist. CONCLUSIONS AND IMPLICATIONS: D2 receptors control pancreatic inflammation in AP by inhibiting NF-κB activation via a PP2A-dependent Akt signalling pathway.