Interleukin-6 modulates oxidative stress produced during the development of cisplatin nephrotoxicity

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• 作者：Satoru Mitazaki^a ; Midori Hashimoto^a ; Yui Matsuhashi^a ; Shigeyoshi Honma^b ; Miwako Suto^c ; Naho Kato^c ; Osamu Nakagawasai^d ; Koichi Tan-No^d ; Kouichi Hiraiwa^c ; Makoto Yoshida^b ; Sumiko Abe^a ; ^{sabe@takasaki-u.ac.jp}
• 关键词：Cisplatin ; IL-6 ; Hydroxyl radical ; Dimethylthiourea ; Nrf2 ; HO-1
• 刊名：Life Sciences
• 出版年：2013
• 出版时间：9 April, 2013
• 年：2013
• 卷：92
• 期：12
• 页码：694-700
• 全文大小：807 K

文摘

Aims

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.

Main methods

WT and IL-6^?/? male mice were given either cisplatin (30 mg/kg) or saline intraperitoneally. DMTU (100 mg/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.

Key findings

In WT mice, DMTU markedly improved cisplatin-induced renal dysfunction and survival rate. DMTU reduced the expression levels of TNF-¦Á, Bax and c-fos and increased the expression levels of IL-6, Bcl-x_L 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-¦Á, Bax and c-fos, but not Bcl-x_L 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.

Significance

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.