Sun Ya Mei, Zheng Shuai, Chen Xue, Gao Feng, Zhang Jie
Department of Gastroenterology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, China.
Front Physiol. 2020 Jan 9;10:1549. doi: 10.3389/fphys.2019.01549. eCollection 2019.
Nuclear receptor subfamily 5 group A member 2 (Nr5a2) is widely involved in the physiological and pathological processes of the pancreas. However, the cytological and molecular evidence regarding how Nr5a2 implicated in acute pancreatitis (AP) remains insufficient. Here, we explored this problem by using cellular AP model in both normal and Nr5a2 silenced AR42J pancreatic acinar cells. An cellular model of AP was established by stimulating AR42J cells with caerulein (CAE) for 24 h. Reduced Nr5a2 expression was observed in the CAE-treated cells. Nr5a2 silencing led to AP-like inflammation, with increased interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α mRNA levels. In the cellular AP model, Nr5a2 silencing further increased IL-1β, IL-6, and TNF-α mRNA levels, as well as amylase activity. In addition, we found that Nr5a2 silencing did not affect IL-10 level under physiological conditions but inhibited the anti-inflammatory response of IL-10 in AP model. Moreover, in CAE-induced pancreatic inflammation, Nr5a2 silencing increased the apoptosis and necrosis of acinar cells and inhibited the proliferation of acinar cells, which has not been shown previously. Further experiments showed, for the first time, that Nr5a2 silencing downregulated the expression of β-catenin and its downstream target gene T-cell factor (TCF)-4 in the cellular AP model but increased the expression of nuclear factor (NF)-κB. In conclusion, in CAE-induced pancreatic inflammation, lower Nr5a2 level leads to downregulation of β-catenin and its downstream target gene TCF-4 and upregulation of NF-κB, which exacerbates the inflammatory response and cell damage and inhibits the proliferation and regeneration of acinar cells.
核受体亚家族5 A组成员2（Nr5a2）广泛参与胰腺的生理和病理过程。然而，关于Nr5a2如何参与急性胰腺炎（AP）的细胞学和分子证据仍然不足。在这里，我们通过在正常和Nr5a2沉默的AR42J胰腺腺泡细胞中使用细胞AP模型来探讨这个问题。通过用雨蛙素（CAE）刺激AR42J细胞24小时建立AP细胞模型。在CAE处理的细胞中观察到Nr5a2表达降低。Nr5a2沉默导致AP样炎症，白细胞介素（IL）-1β、IL-6和肿瘤坏死因子（TNF）-α mRNA水平升高。在细胞AP模型中，Nr5a2沉默进一步增加了IL-1β、IL-6和TNF-α mRNA水平以及淀粉酶活性。此外，我们发现Nr5a2沉默在生理条件下不影响IL-10水平，但在AP模型中抑制了IL-10的抗炎反应。此外，在CAE诱导的胰腺炎症中，Nr5a2沉默增加了腺泡细胞的凋亡和坏死，并抑制了腺泡细胞的增殖，这在以前尚未见报道。进一步的实验首次表明，在细胞AP模型中，Nr5a2沉默下调了β-连环蛋白及其下游靶基因T细胞因子（TCF）-4的表达，但增加了核因子（NF）-κB的表达。总之，在CAE诱导的胰腺炎症中，较低的Nr5a2水平导致β-连环蛋白及其下游靶基因TCF-4的下调和NF-κB的上调，这加剧了炎症反应和细胞损伤，并抑制了腺泡细胞的增殖和再生。
