title: Role of interleukin-6 in the radiation response of liver tumors.
abstract: OBJECTIVE
  To investigate the role of interleukin (IL)-6 in biological sequelae and tumor regrowth after irradiation for hepatic malignancy, which are critical for the clinical radiation response of liver tumors.
  
  
  METHODS
  The Hepa 1-6 murine hepatocellular cancer cell line was used to examine the radiation response by clonogenic assays and tumor growth delay in vivo. After irradiation in a single dose of 6 Gy in vitro or 15 Gy in vivo, biological changes including cell death and tumor regrowth were examined by experimental manipulation of IL-6 signaling. The effects of blocking IL-6 were assessed by cells preincubated in the presence of IL-6-neutralizing antibody for 24 hours or stably transfected with IL-6-silencing vectors. The correlations among tumor responses, IL-6 levels, and myeloid-derived suppressor cells (MDSC) recruitment were examined using animal experiments.
  
  
  RESULTS
  Interleukin-6 expression was positively linked to irradiation and radiation resistance, as demonstrated by in vitro and in vivo experiments. Interleukin-6-silencing vectors induced more tumor inhibition and DNA damage after irradiation. When subjects were irradiated with a sublethal dose, the regrowth of irradiated tumors significantly correlated with IL-6 levels and MDSC recruitment in vivo. Furthermore, blocking of IL-6 could overcome irradiation-induced MDSC recruitment and tumor regrowth after treatment.
  
  
  CONCLUSIONS
  These data demonstrate that IL-6 is important in determining the radiation response of liver tumor cells. Irradiation-induced IL-6 and the subsequent recruitment of MDSC could be responsible for tumor regrowth. Therefore, treatment with concurrent IL-6 inhibition could be a potential therapeutic strategy for increasing the radiation response of tumors.
authors.affiliation: Department of Radiation Oncology, Chang Gung Memorial Hospital, Chiayi, Taiwan. miaofen@adm.cgmh.org.tw
authors.forename: Miao-Fen
authors.initials: MF
authors.lastname: Chen
authors.forename: Ching-Chuan
authors.initials: CC
authors.lastname: Hsieh
authors.forename: Wen-Cheng
authors.initials: WC
authors.lastname: Chen
authors.forename: Chia-Hsuan
authors.initials: CH
authors.lastname: Lai
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D054443:Cell Migration Assays; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D004249:DNA Damage; D015850:Interleukin-6 / Q000494:pharmacology / Q000502:physiology; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D051379:Mice; D022423:Myeloid Cells / Q000187:drug effects / Q000502:physiology*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D009364:Neoplasm Recurrence, Local / Q000378:metabolism / Q000473:pathology; D011836:Radiation Tolerance / Q000502:physiology*; D000093242:Interleukin-6 Inhibitors
chemical_list: D015850:Interleukin-6; D009363:Neoplasm Proteins; D000093242:Interleukin-6 Inhibitors