Dopamine D2 receptor signalling controls inflammation in acute pancreatitis via a PP2A-dependent Akt/NF-κB signalling pathway
Dopamine D2 receptor signalling controls inflammation in acute pancreatitis via a PP2A-dependent Akt/NF-κB signalling pathway
复制标题
多巴胺 D-2 受体信号通过 PP2A 依赖性 Akt/NF-kappa B 信号通路控制急性胰腺炎的炎症
DOI：
10.1111/bph.14057
复制
发表时间：
2017-12-01
影响因子：
7.3
通讯作者：
Hu, Guoyong
中科院分区：
文献类型：
--
作者：
Han, Xiao;Li, Bin;Hu, Guoyong
背景与结论多巴胺具有多种抗炎作用，但其在急性胰腺炎（AP）中的作用及其分子机制尚不清楚。我们研究了多巴胺信号传导在AP炎症反应中的作用。实验方法在野生型和胰腺特异性Drd 2（-/-）小鼠中分析了胰腺多巴胺能系统的变化以及多巴胺、D-1和D-2多巴胺受体的拮抗剂和激动剂的作用。通过测量血清淀粉酶和脂肪酶以及组织学评估来评估胰腺炎的严重程度。NF-κ B B信号通路被评估，巨噬细胞和中性粒细胞迁移被Transwell检测。关键词：AP胰腺多巴胺合成酶和代谢酶水平升高，而D-1和D-2受体水平降低。多巴胺通过抑制NF-κ B B通路减少CCK刺激的胰腺腺泡细胞的炎症。此外，多巴胺的保护作用被D-2拮抗剂阻断，而不是D-1拮抗剂。D-2激动剂降低AP中的胰腺损伤和p-I κ B α、p-NF-κ Bp 65、TNF α、IL-1 β和IL-6的水平。胰腺特异性Drd 2（-/-）加重AP。此外，D-2激动剂激活PP 2A并抑制Akt、IKK、I κ B α和NF-κ B的磷酸化以及炎性细胞因子和趋化因子的产生。此外，它通过降低CCL 2和CXCL 2的表达来抑制巨噬细胞和中性粒细胞的迁移。PP 2A抑制剂衰减这些保护作用的D-2 agonist.CONCLUSIONS和IMPLICATIONSD-2受体控制胰腺炎AP通过抑制NF-κ B B激活通过PP 2A依赖性Akt信号通路。
BACKGROUND AND PURPOSEDopamine hasmultiple anti-inflammatory effects, but its role andmolecularmechanism in acute pancreatitis (AP) are unclear. We investigated the role of dopamine signalling in the inflammatory response in AP.EXPERIMENTAL APPROACHChanges in pancreatic dopaminergic system and effects of dopamine, antagonists and agonists of D-1 and D-2 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-kappa B signalling pathway was evaluated, and macrophage and neutrophil migration assessed by Transwell assay.KEY RESULTSPancreatic dopamine synthetase andmetabolic enzyme levels were increased, whereas D-1 and D-2 receptors were decreased in AP. Dopamine reduced inflammation in CCK-stimulated pancreatic acinar cells by inhibiting the NF-kappa B pathway. Moreover, the protective effects of dopamine were blocked by a D-2 antagonist, but not a D-1 antagonist. A D-2 agonist reduced pancreatic damage and levels of p-I kappa B alpha, p-NF-kappa Bp65, TNF alpha, IL-1 beta and IL-6 in AP. Pancreas-specific Drd2(-/-) aggravated AP. Also, the D-2 agonist activated PP2A and inhibited the phosphorylation of Akt, IKK, I kappa B alpha and NF-kappa 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 D-2 agonist.CONCLUSIONS AND IMPLICATIONSD-2 receptors control pancreatic inflammation in AP by inhibiting NF-kappa B activation via a PP2A-dependent Akt signalling pathway.