TLR4-dependant immune response, but not hepatitis B virus reactivation, is important in radiation-induced liver disease of liver cancer radiotherapy
TLR4-dependant immune response, but not hepatitis B virus reactivation, is important in radiation-induced liver disease of liver cancer radiotherapy
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DOI：
10.1007/s00262-013-1504-9
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发表时间：
2014-03-01
影响因子：
5.8
通讯作者：
Zeng, Zhao-Chong
中科院分区：
文献类型：
--
作者：
Wu, Zhi-Feng;Zhou, Xiao-Hui;Zeng, Zhao-Chong
Toll样受体4(Toll-like Receptor 4，TLR4)是机体抗乙肝病毒感染和肝损伤免疫反应的重要触发因子。乙肝病毒的重新激活与TLR4依赖的免疫反应的作用可能是预防肝癌放射治疗后放射性肝病的关键因素。本研究分为三个阶段。在第一阶段，突变的TLR4(TLR4(-))小鼠的肝脏在没有或有乙肝病毒感染的情况下接受30Gy射线照射。后者通过导入pAAV/HBV1.2质粒来完成。在晚期，比较正常TLR4(TLR4(+))和TLR4(-)小鼠的RILDs。在验证阶段，纳入了28名在肝切除术前接受过放射治疗的肝癌患者。肿瘤附近的肝活检组织经35~48Gy射线照射后用于构建组织芯片。在小鼠和人中研究了乙肝病毒的重新激活、TLR4的表达和RILDs的严重程度。与未照射的TLR4(-)小鼠相比，接受照射的TLR4(-)小鼠有更多的乙肝病毒重新激活，但没有明显的rILD。TLR4(+)组RILD评分高于TLR4(-)组。在人类中，严重的RILD倾向于TLR4高表达的患者，而不是低TLR4或高HBV膜抗原表达的患者。TLR4在12例乙肝病毒反应患者中仅有2例高表达，而在9例无反应患者中有6例高表达(P<；0.03)。总之，RILDs与TLR4的高表达有关，但与乙肝病毒的重新激活无关，后者在肝癌放疗后TLR4高表达的肝脏中被抑制。
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.