title: Deletion of interleukin-6 in monocytes/macrophages suppresses the initiation of hepatocellular carcinoma in mice.
abstract: Hepatocellular carcinoma (HCC) is associated with inflammation, and roughly 30 % of the global population shows serological evidence of current or past infection with hepatitis B or hepatitis C virus. Resident hepatic macrophages, known as Kupffer cells (KCs), are considered as the specific tumor-associated macrophages (TAMs) of HCC, and can produce various cytokines-most importantly interleukin (IL)-6-to promote tumorigenesis of HCC. However, the roles of KCs and IL-6 in carcinogenesis in the liver are still unclear.
  
  
  
  We analyzed leukocyte-related peripheral blood data of 192 patients and constructed a mouse model in which the bone marrow was cleared out by irradiation and reconstructed using bone marrow donated from IL-6-deficient mice to further elucidate the hepatic pathological changes in response to toxic challenge and oncogenic gene mutation.
  
  
  
  Peripheral monocyte counts and serum IL-6 levels were significantly higher in patients with HCC than in those without HCC. In addition, there was a significant difference in the levels of IL-6 among individuals with different histopathological grades. In mice with selective IL-6 ablation in monocytes/KCs, we observed decreased toxic liver injury, inflammatory infiltration, and systemic inflammation. In Mdr2-deficient mice, which spontaneously developed HCC, the loss of IL-6 in monocytes/KCs resulted in inhibition of IL-6/signal transducer and activator of transcription 3 signaling, decreased serum IL-6 levels, and delayed tumorigenesis.
  
  
  
  Our findings demonstrate that increased TAM-derived IL-6 had an amplifying effect on the inflammation response, thereby promoting the occurrence and development of HCC.
authors: Department of Hepato-Biliary-Pancreatic Surgery, West China Hospital of Sichuan University, Chengdu, 610041, China.
authors: Lingxiang
authors: L
authors: Kong
authors: Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, 610041, China.|Key Laboratory of Transplant Engineering and Immunology, Ministry of Health, Chengdu, 610041, China.
authors: Yongjie
authors: Y
authors: Zhou
authors: Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, 610041, China.|Key Laboratory of Transplant Engineering and Immunology, Ministry of Health, Chengdu, 610041, China.
authors: Hong
authors: H
authors: Bu
authors: Department of Hepato-Biliary-Pancreatic Surgery, West China Hospital of Sichuan University, Chengdu, 610041, China.
authors: Tao
authors: T
authors: Lv
authors: Department of Hepato-Biliary-Pancreatic Surgery, West China Hospital of Sichuan University, Chengdu, 610041, China. shiyujun@scu.edu.cn.|Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, 610041, China. shiyujun@scu.edu.cn.
authors: Yujun
authors: Y
authors: Shi
authors: Department of Hepato-Biliary-Pancreatic Surgery, West China Hospital of Sichuan University, Chengdu, 610041, China. yangjygyz@163.com.
authors: Jiayin
authors: J
authors: Yang
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000172:deficiency; D000328:Adult; D000368:Aged; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000097:blood / Q000235:genetics / Q000276:immunology*; D005260:Female; D017353:Gene Deletion; D006801:Humans; D015850:Interleukin-6 / Q000097:blood / Q000235:genetics*; D007728:Kupffer Cells / Q000276:immunology*; D007958:Leukocyte Count; D008113:Liver Neoplasms / Q000097:blood / Q000235:genetics* / Q000276:immunology; D008297:Male; D051379:Mice; D008875:Middle Aged; D009374:Neoplasms, Experimental; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D015850:Interleukin-6; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C508600:IL6 protein, human; C577686:interleukin-6, mouse
keywords: Hepatocellular carcinoma (HCC); Inflammation; Interleukin- 6 (IL-6); Tumor associated macrophage (TAM)