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Cancer Immunology, Immunotherapy

, Volume 63, Issue 3, pp 235–245 | Cite as

TLR4-dependant immune response, but not hepatitis B virus reactivation, is important in radiation-induced liver disease of liver cancer radiotherapy

  • Zhi-Feng Wu
  • Xiao-Hui Zhou
  • Yun-Wen Hu
  • Le-Yuan Zhou
  • Ya-Bo Gao
  • Xiu-Hua Peng
  • Xiao-Hua Yang
  • Jian-Ying Zhang
  • Yong Hu
  • Zhao-Chong ZengEmail author
Original Article

Abstract

Toll-like receptor 4 (TLR4) is an important trigger of the immune response against hepatitis B virus (HBV) infection and liver injuries. The roles of HBV reactivation versus TLR4-dependant immune response may be critical factors in preventing radiation-induced liver diseases (RILDs) after liver cancer radiotherapy. This study consists of three phases. In the primary phase, livers of mutant TLR4 (TLR4) mice were irradiated with 30 Gy in either the absence or presence of HBV infection. The latter was done by introduction of plasmid pAAV/HBV 1.2. In the advanced phase, RILDs were compared in normal TLR4 (TLR4+) versus TLR4 mice. In the validation phase, 28 liver cancer patients who had undergone radiotherapy before hepatectomy were enrolled. Liver biopsies near tumors, irradiated with 35–48 Gy, were used to construct tissue microarrays. HBV reactivation, TLR4 expression, and severity of RILDs were studied in both mouse and human. More HBV reactivation, without significant RILD, was observed in irradiated versus unirradiated TLR4 mice. RILD scores of TLR4+ mice were higher than TLR4 mice. In humans, serious RILDs tended to develop in patients with high TLR4 expression, but not in patients with low TLR4 or high HBV surface antigen expression. High TLR4 expression was seen in only 2 of 12 HBV-reactive patients, but in HBV-nonreactive patients, it was seen in 6 of 9 (P < 0.03). In summary, RILDs correlated with high TLR4 expression, but not with HBV reactivation, which is inhibited in liver with high TLR4 expression after liver cancer radiotherapy.

Keywords

Hepatitis B virus Liver cancer Toll-like receptor TLR4 mutation Radiotherapy 

Abbreviations

HBV

Hepatitis B virus

RILD

Radiation-induced liver disease

TLR4

Toll-like receptor 4

RT

Radiotherapy

HCC

Hepatocellular carcinoma

HBsAg

Hepatitis B surface antigen

PCR

Polymerase chain reaction

TMA

Tissue microarray

IL

Interleukin

IFN

Interferon

Notes

Acknowledgments

We thank Prof. Pei-Jer Chen (National Taiwan University) for kindly providing plasmid pAAV/HBV 1.2. This work was supported by the National Natural Science Foundation of China (Grant 81241012 to Z–C Zeng).

Conflict of interest

None.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Zhi-Feng Wu
    • 1
  • Xiao-Hui Zhou
    • 2
  • Yun-Wen Hu
    • 3
  • Le-Yuan Zhou
    • 1
  • Ya-Bo Gao
    • 1
  • Xiu-Hua Peng
    • 2
  • Xiao-Hua Yang
    • 4
  • Jian-Ying Zhang
    • 1
  • Yong Hu
    • 1
  • Zhao-Chong Zeng
    • 1
    Email author
  1. 1.Department of Radiation Oncology, Zhongshan HospitalFudan UniversityShanghaiChina
  2. 2.Shanghai Public Health Clinical CenterFudan UniversityShanghaiChina
  3. 3.Key Laboratory of Medical Molecular Virology of the Ministries of EducationFudan UniversityShanghaiChina
  4. 4.Shanghai Chest HospitalShanghai Jiaotong UniversityShanghaiChina

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