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

ABSTRACT:

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-?B 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-?B 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-I?B?, p-NF-?Bp65, TNF?, IL-1? and IL-6 in AP. Pancreas-specific Drd2^-/- aggravated AP. Also, the D₂ agonist activated PP2A and inhibited the phosphorylation of Akt, IKK, I?B? and NF-?B 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-?B activation via a PP2A-dependent Akt signalling pathway.

SUBMITTER: Han X 

PROVIDER: S-EPMC5727253 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature