野崎 祐史; 木下 浩二; 矢野 智洋; 朝戸 佳世; 志賀 俊彦; 樋野 尚一; 仁木 かをる; 廣岡 靖章; 岸本 和也; 嶋津 秀紀; 船内 正憲; 松村 到
Kidney International 82 8 892 - 902 2012年10月
Interleukin (IL)-18 is produced by leukocytes and renal parenchymal cells (tubular epithelial cells, podocytes, and mesangial cells). The IL-18 receptor (IL-18R) is expressed on these cells in cisplatin-induced acute kidney injury, but the role of IL-18R is unknown. To help define this, we compared IL-18R alpha knockout with wild-type mice in cisplatin-induced acute kidney injury and found deteriorated kidney function, tubular damage, increased accumulation of leukocytes (CD4(+) and CD8(+) T-cells, macrophages, and neutrophils), upregulation of early kidney injury biomarkers (serum TNF, urinary IL-18, and KIM-1 levels), and increased expression of pro-inflammatory molecules downstream of IL-18. In vitro, leukocytes from the spleen and kidneys of the knockout mice produced greater amounts of pro-inflammatory cytokines upon stimulation with concanavalin A compared to that in wild-type mice. Levels of the suppressor of cytokine signaling 1 and 3 (negative regulators of cytokine signaling) were reduced in the spleen and kidneys of IL-18R alpha-deficient compared to wild-type mice. Adoptive transfer of wild-type splenocytes by IL-18R alpha-deficient mice led to decreased cisplatin nephrotoxicity compared to control IL-18R alpha-deficient mice. In contrast, anti-IL-18R alpha and anti-IL-18R beta antibody treatment tended to increase cisplatin nephrotoxicity in wild-type mice. Thus, signaling through IL-18Ra activates both inflammation-suppressing and pro-injury pathways in cisplatin-induced acute kidney injury. Kidney International (2012) 82, 892-902; doi:10.1038/ki.2012.226; published online 6 June 2012