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Radiation-Induced Hepatitis B Virus Reactivation in Liver Mediated by the Bystander Effect from Irradiated Endothelial Cells

Authors' Affiliations: Departments of ¹ Oncology, ² Internal Medicine, and ³ Surgery, National Taiwan University Hospital; ⁴ Graduate Institute of Clinical Medicine and ⁵ Cancer Research Center, National Taiwan University College of Medicine, Taipei, Taiwan

Requests for reprints: Jason Chia-Hsien Cheng, Department of Oncology, National Taiwan University Hospital, No. 7 Chung-Shan South Road, Taipei 100, Taiwan. Phone: 886-2-2312-3456, ext. 6696; Fax: 886-2-2371-1174; E-mail: jasoncheng{at}ha.mc.ntu.edu.tw.

Purpose: Hepatitis B virus (HBV) reactivation is one unique pathogenesis in Asian carriers with liver toxicity after radiotherapy for hepatobiliary malignancies. This study attempts to delineate the biological mechanism of radiation-induced HBV reactivation.

Experimental Design: Primary cultures of hepatocytes (PCC) were prepared from the noncancerous liver tissue removed perioperatively from 12 HBV carriers with hepatocellular carcinoma (HCC). The conditioned medium of irradiated PCCs, HCC, and endothelial cells from patients was transferred to PCCs or HepG2.2.15 cells (a human hepatoblastoma cell line transfected with HBV DNA) before subsequent irradiation. Forty-eight hours after irradiation, HBV DNA was measured by real-time quantitative PCR. Specific cytokines were determined by cytokine array and ELISA analysis. Preradiotherapy and postradiotherapy sera from 10 HBV carriers and 16 non-HBV carriers were analyzed for viral loads and cytokine activities.

Results: Radiation induced HBV DNA replication in (a) irradiated PCCs cultured with the conditioned medium from irradiated PCCs (2.74-fold; P = 0.004) and endothelial cells (9.50-fold; P = 3.1 x 10^–10), but not from HCCs (1.07-fold), and in (b) irradiated HepG2.2.15 cells (17.7-fold) cocultured with human umbilical vascular endothelial cells. Cytokine assay revealed increased expression of interleukin-6 (IL-6) in conditioned medium from irradiated human umbilical vascular endothelial cells. All 16 patients with liver irradiated had the increased serum IL-6 compared with 3 of 10 patients with irradiation excluding liver (P < 0.001). All nine HBV carriers with liver irradiated had postradiotherapy increases in both HBV DNA and IL-6.

Conclusions: Radiation-induced liver toxicity with HBV reactivation is from a bystander effect on irradiated endothelial cells releasing cytokines, including IL-6.