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

Xiao Han, Han X, Bin Li, Li B, Ye X, Xin Ye, Tunike Mulatibieke, Mulatibieke T, Wu J, Jianghong Wu, Juanjuan Dai, Dai J, Deqing Wu, Wu D, Ni J, Jianbo Ni, Zhang R, Ruling Zhang, Xue J, Jing Xue, Rong Wan, Wan R, Xingpeng Wang, Wang X, Hu G
British journal of pharmacology · 2017 · vol. 174(24) , pp. 4751–4770 · doi:10.1111/bph.14057 · PMID:28963856 · PMC5727253
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Dopamine D2 receptor signaling reduces acute pancreatitis inflammation by inhibiting the NF-κB pathway through a PP2A-dependent Akt mechanism, thereby suppressing cytokine production and immune cell migration.

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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-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.

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MeSH descriptors

Inflammation NF-kappa B Pancreatitis Protein Phosphatase 2 Proto-Oncogene Proteins c-akt Receptors, Dopamine D2 Acute Disease Animals Humans Inflammation Male Mice Mice, Inbred BALB C Mice, Inbred C57BL Mice, Knockout NF-kappa B Pancreatitis Protein Phosphatase 2 Proto-Oncogene Proteins c-akt Receptors, Dopamine D2

Funding

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[{'doi': '10.13039/501100001809', 'name': 'National Natural Science Foundation of China', 'awards': ['81370568']}, {'doi': '10.13039/501100001809', 'name': 'National Natural Science Foundation of China', 'awards': ['81372643']}, {'doi': '10.13039/501100001809', 'name': 'National Natural Science Foundation of China', 'awards': ['81400663']}, {'doi': '10.13039/501100001809', 'name': 'National Natural Science Foundation of China', 'awards': ['81570580']}, {'doi': '10.13039/501100001809', 'name': 'National Natural Science Foundation of China', 'awards': ['81670584']}]

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