Wang Qinghua, Bai Lichuan, Luo Shuya, Wang Tianyu, Yang Fan, Xia Jialin, Wang Hui, Ma Ke, Liu Mei, Wu Shuwei, Wang Huijie, Guo Shibin, Sun Xiaohong, Xiao Qinghuan
Department of Ion Channel Pharmacology, School of Pharmacy, China Medical University, Shenyang 110122, China.
Department of Experimental Center, The Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang 110032, China.
J Adv Res. 2020 Jan 21;23:25-35. doi: 10.1016/j.jare.2020.01.006. eCollection 2020 May.
TMEM16A Ca-activated Cl channels are expressed in pancreatic acinar cells and participate in inflammation-associated diseases. Whether TMEM16A contributes to the pathogenesis of acute pancreatitis (AP) remains unknown. Here, we found that increased TMEM16A expression in the pancreatic tissue was correlated with the interleukin-6 (IL-6) level in the pancreatic tissue and in the serum of a cerulein-induced AP mouse model. IL-6 treatment promoted TMEM16A expression in AR42J pancreatic acinar cells via the IL-6 receptor (IL-6R)/signal transducers and activators of transcription 3 (STAT3) signaling pathway. In addition, TMEM16A was co-immunoprecipitated with the inositol 1,4,5-trisphosphate receptor (IPR) and was activated by IPR-mediated Ca release. TMEM16A inhibition reduced the IPR-mediated Ca release induced by cerulein. Furthermore, TMEM16A overexpression activated nuclear factor-κB (NFκB) and increased IL-6 release by increasing intracellular Ca. TMEM16A knockdown by shRNAs reduced the cerulein-induced NFκB activation by Ca. TMEM16A inhibitors inhibited NFκB activation by decreasing channel activity and reducing TMEM16A protein levels in AR42J cells, and it ameliorated pancreatic damage in cerulein-induced AP mice. This study identifies a novel mechanism underlying the pathogenesis of AP by which IL-6 promotes TMEM16A expression via IL-6R/STAT3 signaling activation, and TMEM16A overexpression increases IL-6 secretion via IPR/Ca/NFκB signaling activation in pancreatic acinar cells. TMEM16A inhibition may be a new potential strategy for treating AP.
跨膜蛋白16A（TMEM16A）钙激活氯离子通道在胰腺腺泡细胞中表达，并参与炎症相关疾病。TMEM16A是否参与急性胰腺炎（AP）的发病机制尚不清楚。在此，我们发现胰腺组织中TMEM16A表达的增加与雨蛙素诱导的AP小鼠模型的胰腺组织及血清中的白细胞介素-6（IL-6）水平相关。IL-6处理通过IL-6受体（IL-6R）/信号转导子和转录激活子3（STAT3）信号通路促进AR42J胰腺腺泡细胞中TMEM16A的表达。此外，TMEM16A与肌醇1,4,5-三磷酸受体（IPR）共免疫沉淀，并被IPR介导的钙释放激活。TMEM16A抑制减少了雨蛙素诱导的IPR介导的钙释放。此外，TMEM16A过表达激活核因子-κB（NFκB），并通过增加细胞内钙来增加IL-6释放。通过短发夹RNA（shRNA）敲低TMEM16A可减少雨蛙素诱导的钙依赖性NFκB激活。TMEM16A抑制剂通过降低通道活性和降低AR42J细胞中TMEM16A蛋白水平来抑制NFκB激活，并改善雨蛙素诱导的AP小鼠的胰腺损伤。本研究确定了AP发病机制的一种新机制，即IL-6通过IL-6R/STAT3信号激活促进TMEM16A表达，而TMEM16A过表达通过IPR/钙/NFκB信号激活增加胰腺腺泡细胞中IL-6分泌。抑制TMEM16A可能是治疗AP的一种新的潜在策略。
