TY - JOUR
T1 - Hepatitis B virus enhances tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) cytotoxicity by increasing TRAIL-R1/death receptor 4 expression
AU - Janssen, Harry L.A.
AU - Higuchi, Hajime
AU - Abdulkarim, Ahmad
AU - Gores, Gregory J.
N1 - Funding Information:
This work was supported by a Grant from the National Institute of Health (DK41876), the Mayo Foundation, the Erasmus University Trust Foundation Rotterdam, the Netherlands Foundation for Digestive Diseases (MLDS). We are indebted to Pavel Taimr, Bert Niesters, Patrick van Bergen, Ruud Heijtink, Steve Bronk, Nathan Werneburg and M. Eugenia Guicciardi for their support. Dr Janssen is a Fellow of the Netherlands Organisation for Scientific Research (NWO).
PY - 2003/9/1
Y1 - 2003/9/1
N2 - Background/Aims: Apoptosis by death receptors, such as Fas and tumor necrosis factor (TNF)-alpha receptor-1, play a significant role in the pathogenesis of hepatitis B virus (HBV)-infections. Although liver also expresses death receptors for TNF-related apoptosis-inducing ligand (TRAIL), information is lacking regarding the effects of HBV on apoptosis by TRAIL. Thus, the aims of this study were to examine the effects of HBV replication on TRAIL cytotoxicity. Methods: Hep G2 and Hep G2.215 cells, the latter which is stably transfected with HBV, were employed for these studies. Results: TRAIL-mediated cell killing was concentration-dependent and greater in Hep G2.2.15 cells at all doses as compared to the parent cell line, Hep G2 cells. Cell death by apoptosis was confirmed by demonstrating caspase activation and inhibition of cell killing by a caspase inhibitor, zVAD-fmk. TRAIL-R1/DR4 protein expression was enhanced in Hep G2.2.15 cells as compared to Hep G2 cells. Lamivudine treatment reduced TRAIL-mediated apoptosis and TRAIL-R1/DR4 expression in Hep G2.2.15 cells. In Hep G2 cells transfected with the HBV-encoded X antigen (HBxAg), sensitivity to TRAIL-mediated apoptosis and TRAIL-R1/DR4 expression were both increased. Conclusions: TRAIL-induced apoptosis is enhanced by the level of HBV replication in human hepatocytes, in part, by HBxAg-dependent upregulation of TRAIL-R1/DR4.
AB - Background/Aims: Apoptosis by death receptors, such as Fas and tumor necrosis factor (TNF)-alpha receptor-1, play a significant role in the pathogenesis of hepatitis B virus (HBV)-infections. Although liver also expresses death receptors for TNF-related apoptosis-inducing ligand (TRAIL), information is lacking regarding the effects of HBV on apoptosis by TRAIL. Thus, the aims of this study were to examine the effects of HBV replication on TRAIL cytotoxicity. Methods: Hep G2 and Hep G2.215 cells, the latter which is stably transfected with HBV, were employed for these studies. Results: TRAIL-mediated cell killing was concentration-dependent and greater in Hep G2.2.15 cells at all doses as compared to the parent cell line, Hep G2 cells. Cell death by apoptosis was confirmed by demonstrating caspase activation and inhibition of cell killing by a caspase inhibitor, zVAD-fmk. TRAIL-R1/DR4 protein expression was enhanced in Hep G2.2.15 cells as compared to Hep G2 cells. Lamivudine treatment reduced TRAIL-mediated apoptosis and TRAIL-R1/DR4 expression in Hep G2.2.15 cells. In Hep G2 cells transfected with the HBV-encoded X antigen (HBxAg), sensitivity to TRAIL-mediated apoptosis and TRAIL-R1/DR4 expression were both increased. Conclusions: TRAIL-induced apoptosis is enhanced by the level of HBV replication in human hepatocytes, in part, by HBxAg-dependent upregulation of TRAIL-R1/DR4.
KW - Apoptosis
KW - Lamivudine
UR - http://www.scopus.com/inward/record.url?scp=0042329166&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0042329166&partnerID=8YFLogxK
U2 - 10.1016/S0168-8278(03)00265-4
DO - 10.1016/S0168-8278(03)00265-4
M3 - Article
C2 - 12927928
AN - SCOPUS:0042329166
SN - 0168-8278
VL - 39
SP - 414
EP - 420
JO - Journal of Hepatology
JF - Journal of Hepatology
IS - 3
ER -