Hepatitis C-induced hepatocyte cell death and protection by inhibition of apoptosis

Lim, EJ; El Khobar, K; Chin, R; Earnest-Silveira, L; Angus, PW; Bock, CT; Nachbur, U; Silke, J; Torresi, J

Author(s): Lim, EJ; El Khobar, K; Chin, R; Earnest-Silveira, L; Angus, PW; Bock, CT; Nachbur, U; Silke, J; Torresi, J;
Details: Publication Year 2014-06-27,Volume 95,Issue #10,Page 2204-2215
Journal Title: J Gen Virol
Publication Type: Journal Article
Abstract: Background: Chronic hepatitis C (HCV) results in progressive liver fibrosis leading to cirrhosis and liver cancer. The mechanism for this remains unclear but hepatocyte apoptosis is thought to play a major role. Methods: Hepatocyte apoptosis in human liver tissue was determined by immunohistochemistry for M30 cytoDEATH and cleaved PARP. In vitro studies were performed with replication-defective recombinant adenoviruses expressing HCV proteins (rAdHCV) to study the effects of HCV on cell death in Huh7 cells, and primary mouse (PMoH) and human hepatocytes (PHH). Cell viability and apoptosis were studied using crystal violet assays and Western immunoblots probed for cleaved caspase 3 and cleaved PARP, with and without treatment with Q-VD-Oph and necrostatin-1. Results: Liver tissue of HCV-infected patients expressed elevated levels of apoptotic markers compared to HCV-negative patients. rAdHCV infection reduced cell viability compared to uninfected controls and cells infected with control virus (rAdGFP). Huh7, PMoH and PHH infected with rAdHCV showed significantly increased levels of apoptotic markers compared to uninfected controls and rAdGFP-infected cells. In rAdHCV-infected Huh7, treatment with Q-VD-Oph and necrostatin-1 both improved cell viability. Q-VD-Oph also reduced cleaved PARP in rAdHCV-infected Huh7 and PMoH. Conclusions: Hepatocyte apoptosis is increased in the livers of HCV-infected patients. HCV promoted cell death in primary and immortalized hepatocytes and this was inhibited by Q-VD-Oph and necrostatin-1. These findings indicate that HCV-induced cell death occurs by both apoptosis and necroptosis and provide new insights into the mechanisms of HCV-induced liver injury.
Publisher: Society for General Microbiology
Research Division(s): Cell Signalling And Cell Death
PubMed ID: 24973240
Publisher's Version: https://doi.org/10.1099/vir.0.065862-0
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2014-06-30 08:31:35

Last Modified: 2016-05-05 03:23:18