HCV induces transforming growth factor β1 through activation of endoplasmic reticulum stress and the unfolded protein response

• Main Authors: Pattranuch Chusri, Kattareeya Kumthip, Jian Hong, Chuanlong Zhu, Xiaoqiong Duan, Nikolaus Jilg, Dahlene N. Fusco, Cynthia Brisac, Esperance A. Schaefer, Dachuan Cai, Lee F. Peng, Niwat Maneekarn, Wenyu Lin, Raymond T. Chung
• Format: Journal
• Published: 2018
• Subjects: Multidisciplinary
• Online Access: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84959467728&origin=inward; http://cmuir.cmu.ac.th/jspui/handle/6653943832/56372
• Institution: Chiang Mai University

HCV replication disrupts normal endoplasmic reticulum (ER) function and activates a signaling network called the unfolded protein response (UPR). UPR is directed by three ER transmembrane proteins including ATF6, IRE1, and PERK. HCV increases TGF-β1 and oxidative stress, which play important roles in liver fibrogenesis. HCV has been shown to induce TGF-β1 through the generation of reactive oxygen species (ROS) and p38 MAPK, JNK, ERK1/2, and NFκB-dependent pathways. However, the relationship between HCV-induced ER stress and UPR activation with TGF-β1 production has not been fully characterized. In this study, we found that ROS and JNK inhibitors block HCV up-regulation of ER stress and UPR activation. ROS, JNK and IRE1 inhibitors blocked HCV-activated NFκB and TGF-β1 expression. ROS, ER stress, NFκB, and TGF-β1 signaling were blocked by JNK specific siRNA. Knockdown IRE1 inhibited JFH1-activated NFκB and TGF-β1 activity. Knockdown of JNK and IRE1 blunted JFH1 HCV up-regulation of NFκB and TGF-β1 activation. We conclude that HCV activates NFκB and TGF-β1 through ROS production and induction of JNK and the IRE1 pathway. HCV infection induces ER stress and the UPR in a JNK-dependent manner. ER stress and UPR activation partially contribute to HCV-induced NF-κB activation and enhancement of TGF-β1.