title: Interleukin-6 modulates oxidative stress produced during the development of cisplatin nephrotoxicity.
abstract: OBJECTIVE
  We reported that interleukin-6 (IL-6) plays a protective role in the development of cisplatin-induced acute renal failure (ARF) through upregulation of anti-oxidative stress factors. In this study, we examined the effects of dimethylthiourea (DMTU), a hydroxyl radical scavenger, on the development of cisplatin-induced ARF in wild-type (WT) and IL-6(-/-) mice to determine how IL-6 contributes to modulation of oxidative stress caused by cisplatin.
  
  
  METHODS
  WT and IL-6(-/-) male mice were given either cisplatin (30 mg/kg) or saline intraperitoneally. DMTU (100mg/kg) or saline was given 30 min before cisplatin or saline administration. Blood and kidney samples were collected on days 1 and 3 after cisplatin administration.
  
  
  RESULTS
  In WT mice, DMTU markedly improved cisplatin-induced renal dysfunction and survival rate. DMTU reduced the expression levels of TNF-α, Bax and c-fos and increased the expression levels of IL-6, Bcl-xL and Nrf2 in WT mice. Reduced reactive oxygen species (ROS) by DMTU resulted in increases of IL-6, anti-apoptosis and anti-oxidant gene expression levels. In IL-6(-/-) mice, DMTU also improved cisplatin-induced renal dysfunction and reduced expression levels of TNF-α, Bax and c-fos, but not Bcl-xL and Nrf2. Since Nrf2 induces IL-6 expression, IL-6 and Nrf2 may influence each other during anti-oxidant responses. The basal level of HO-1 in IL-6(-/-) mice was higher than that in WT mice.
  
  
  CONCLUSIONS
  In IL-6(-/-) mice, overproduction of ROS by cisplatin results in upregulation of HO-1 expression in order to eliminate oxidative stress. IL-6 mediates the generation and elimination of ROS during cisplatin-induced ARF.
authors: Laboratory of Forensic Toxicology, Faculty of Pharmacy, Takasaki University of Health and Welfare, 60 Nakaorui-machi, Takasaki 370-0033, Japan.
authors: Satoru
authors: S
authors: Mitazaki
authors: Midori
authors: M
authors: Hashimoto
authors: Yui
authors: Y
authors: Matsuhashi
authors: Shigeyoshi
authors: S
authors: Honma
authors: Miwako
authors: M
authors: Suto
authors: Naho
authors: N
authors: Kato
authors: Osamu
authors: O
authors: Nakagawasai
authors: Koichi
authors: K
authors: Tan-No
authors: Kouichi
authors: K
authors: Hiraiwa
authors: Makoto
authors: M
authors: Yoshida
authors: Sumiko
authors: S
authors: Abe
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D002945:Cisplatin / Q000633:toxicity*; D016166:Free Radical Scavengers / Q000627:therapeutic use; D005786:Gene Expression Regulation / Q000187:drug effects; D055786:Gene Knockout Techniques; D051547:Heme Oxygenase-1 / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000235:genetics; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D013890:Thiourea / Q000031:analogs & derivatives / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D016166:Free Radical Scavengers; D015850:Interleukin-6; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D017382:Reactive Oxygen Species; C038983:1,3-dimethylthiourea; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D013890:Thiourea; D002945:Cisplatin