Heat-Labile Enterotoxin-Induced PERK-CHOP Pathway Activation Causes Intestinal Epithelial Cell Apoptosis

Frontiers in Cellular and Infection Microbiology

Li, Congcong¹  Jin, Faguang²  Fu, Enqing²  Lu, Xi²  Li, Chunmeng³  Li, Pengcheng³  Xie, Yonghong³ 

[1] Bacteriology Room in Department of Clinical Laboratory, Shaanxi Province Hospital of Traditional Chinese Medicine, Xi'Department of Respiration, Tangdu Hospital, Fourth Military Medical University, Xi'an, China

关键词: Enterotoxigenic Escherichia coli;    Heat-labile enterotoxin;    Apoptosis;    Endoplasmic Reticulum Stress;    ROS;   

DOI  :  10.3389/fcimb.2017.00244

学科分类：生物科学（综合）

来源: Frontiers

【 摘 要 】

Abstract Enterotoxigenic Escherichia coli (ETEC) is a leading cause of diarrhea among children and travelers in developing countries, and heat-labile enterotoxin (LT) is one of the most important virulence factors. The pathogenesis of and virulence factors associated with ETEC have been well characterized; however, the extent to which ETEC damages host cells remains unclear. In this study, we found that LT could induce decreases in intestinal epithelial cell viability and induce apoptosis in a dose- and time- dependent manner in both HCT-8 and Caco-2 cells. We analyzed the expression profiles of apoptosis-related proteins via protein array technology and found that Bax, p-p53(S46), cleaved caspase-3 and TNFRI/TNFRSF1A expression levels were significantly up-regulated in wild-type ETEC- but not in ΔLT ETEC-infected HCT-8 cells. Bax is essential for endoplasmic reticulum (ER) stress-triggered apoptosis, and our RNAi experiments showed that the PERK-eIF2-CHOP pathway and reactive oxygen species (ROS) are also main participants in this process. LT-induced ROS generation was decreased in CHOP-knockdown HCT-8 cells compared to that in control cells. Moreover, pretreatment with the ROS inhibitor NAC down-regulated GRP78, CHOP, Bim and cleaved caspase-3 expression, resulting in a reduction in the apoptosis rate from 36.2% to 20.3% in LT-treated HCT-8 cells. Furthermore, ROS inhibition also attenuated LT-induced apoptosis in the small intestinal mucosa in the ETEC-inoculation mouse model.

【 授权许可】

CC BY