The Department of Gerontology, The Third Xiangya Hospital of Central South University, No. 138, Tongzipo Road, Yuelu District, Changsha, 410013, Hunan Province, People's Republic of China.
The Department of Intensive Care Unit (ICU), The Third Xiangya Hospital of Central South University, No. 138, Tongzipo Road, Yuelu District, Changsha, 410013, Hunan Province, People's Republic of China.
Inflamm Res. 2022 Sep;71(9):1067-1078. doi: 10.1007/s00011-022-01609-8. Epub 2022 Jul 28.
Acute pancreatitis (AP) is an inflammatory process of the pancreas resulting from biliary obstruction or alcohol consumption. Approximately, 10-20% of AP can evolve into severe AP (SAP). In this study, we sought to explore the physiological roles of the transcription factor serum response factor (SRF), annexin A2 (ANXA2), and nuclear factor-kappaB (NF-κB) in SAP.
C57BL/6 mice and rat pancreatic acinar cells (AR42J) were used to establish an AP model in vivo and in vitro by cerulein with or without lipopolysaccharide (LPS). Production of pro-inflammatory cytokines (IL-1β and TNF-α) were examined by ELISA and immunoblotting analysis. Hematoxylin and eosin (HE) staining and TUNEL staining were performed to evaluate pathological changes in the course of AP. Apoptosis was examined by flow cytometric and immunoblotting analysis. Molecular interactions were tested by dual luciferase reporter, ChIP, and Co-IP assays.
ANXA2 was overexpressed in AP and correlated to the severity of AP. ANXA2 knockdown rescued pancreatic acinar cells against inflammation and apoptosis induced by cerulein with or without LPS. Mechanistic investigations revealed that SRF bound with the ANXA2 promoter region and repressed its expression. ANXA2 could activate the NF-κB signaling pathway by inducing the nuclear translocation of p50. SRF-mediated transcriptional repression of ANXA2-protected pancreatic acinar cells against AP-like injury through repressing the NF-κB signaling pathway.
Our study highlighted a regulatory network consisting of SRF, ANXA2, and NF-κB that was involved in AP progression, possibly providing some novel targets for treating SAP.
急性胰腺炎（AP）是一种胰腺炎症过程，由胆道阻塞或酒精摄入引起。大约 10-20%的 AP 可发展为重症 AP（SAP）。在这项研究中，我们试图探讨转录因子血清反应因子（SRF）、膜联蛋白 A2（ANXA2）和核因子-κB（NF-κB）在 SAP 中的生理作用。
使用 C57BL/6 小鼠和大鼠胰腺腺泡细胞（AR42J），通过使用 Cerulein 加或不加脂多糖（LPS）在体内和体外建立 AP 模型。通过 ELISA 和免疫印迹分析检测促炎细胞因子（IL-1β和 TNF-α）的产生。通过苏木精和伊红（HE）染色和 TUNEL 染色评估 AP 过程中的病理变化。通过流式细胞术和免疫印迹分析检测细胞凋亡。通过双荧光素酶报告基因、ChIP 和 Co-IP 测定检测分子相互作用。
ANXA2 在 AP 中过度表达，与 AP 的严重程度相关。ANXA2 敲低可挽救胰腺腺泡细胞免受 Cerulein 加或不加 LPS 诱导的炎症和凋亡。机制研究表明，SRF 与 ANXA2 启动子区域结合并抑制其表达。ANXA2 通过诱导 p50 的核易位激活 NF-κB 信号通路。SRF 介导的 ANXA2 转录抑制通过抑制 NF-κB 信号通路保护胰腺腺泡细胞免受 AP 样损伤。
我们的研究强调了由 SRF、ANXA2 和 NF-κB 组成的调控网络参与了 AP 的进展，可能为治疗 SAP 提供了一些新的靶点。
