IL-23 production of liver inflammatory macrophages to damaged hepatocytes promotes hepatocellular carcinoma development after chronic hepatitis B virus infection |
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Authors: | Mengya Zang Yuan Li Huan He Huiguo Ding Kun Chen Jun Du Taoyang Chen Zhiyuan Wu Hui Liu Dongmei Wang Jianqiang Cai Chunfeng Qu |
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Institution: | 1. State Key Laboratory of Molecular Oncology/Department of Immunology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China;2. Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China;3. Gastroenterology and Hepatology Department, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China;4. Qidong Liver Cancer Institute & Qidong People''s Hospital, Qidong, Jiangsu Province 226200, China |
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Abstract: | Liver inflammation after chronic hepatitis B virus (HBV) infection is essential for hepatocellular carcinoma (HCC) development. We did a nested case-control study based on QBC chronic HBV infection cohort to identify HCC-related inflammatory cytokines. Serum levels of distinct Th-cell representative cytokines at varied periods before HCC diagnosis were determined in 50 HCC cases and 150 age- and gender-matched controls who did not develop HCC in 8–10?years. The individuals with HCC outcome had statistically higher serum levels of IL-23 than controls (P?<?0.01). Further analysis in HCC tissues showed that CD14+ inflammatory macrophages were the major IL-23 producers. Monocytes-derived macrophages generated more amount of IL-23 after being stimulated with cell-associated HBV core antigen from damaged HBV-infected hepatocytes than the cells being stimulated with HBV-S and HBV e antigen, which are secreted from infected hepatocytes. IL-23 upregulated IL-23 receptor expressions on macrophages, enhanced macrophage-mediated angiogenesis. In HBV-transgenic (Alb1HBV) mice, administration of diethylnitrosamine induced more liver tumors than in wild-type mice. The livers of Alb1HBV mice had higher concentrations of IL-23 and vascular endothelial growth factor (VEGF) than the wild-type mice. Neutralizing IL-23 activity, diethylnitrosamine-treated Alb1HBV mice developed significantly less tumors and produced less VEGF, tumor angiogenesis was inhibited with dramatically decreased CD31+ cells within tumor mass (all P?<?0.01).ConclusionPersistent IL-23 generation of liver inflammatory macrophages responding to damaged hepatocytes after chronic HBV infection altered macrophage function for HCC promotion. Blocking IL-23 activity might be helpful for the intervention in chronic hepatitis B patients who had high risk to HCC. |
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Keywords: | HCC hepatocellular carcinoma HBV hepatitis B virus HBcAg HBV capsid antigen CHB chronic hepatitis B PBMCs peripheral blood mononuclear cells DEN diethylnitrosamine HUVEC human umbilical vein endothelia cells qRT-PCR quantitative Real-Time PCR GSEA gene set enrichment analysis FCM flow cytometry ALT alanine transaminase MCM macrophage conditioned medium Liver macrophages Interleukin 23 Hepatitis B virus proteins Hepatocellular carcinoma |
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