Department of Urology, James Whitcomb Riley Hospital for Children, Indianapolis, Indiana 46202, USA.
J Urol. 2011 Oct;186(4):1502-8. doi: 10.1016/j.juro.2011.05.046. Epub 2011 Aug 19.
Interleukin-18 is a proinflammatory cytokine that is an important mediator of obstruction induced renal tubulointerstitial fibrosis independent of tumor necrosis factor-α and β1 activity. We hypothesized that interleukin-18 stimulates a positive feedback loop during obstruction via interleukin-18 receptor to increase interleukin-18 gene expression and protein production.
Male C57BL6 interleukin-18 receptor knockout (The Jackson Laboratory, Bar Harbor, Maine) and control wild-type mice underwent unilateral ureteral obstruction or sham operation and were sacrificed 1 week after surgery. Renal cortical tissue samples were harvested and analyzed for interleukin-18 protein by enzyme-linked immunosorbent assay, and for interleukin-18 and interleukin-18 receptor gene expression by quantitative polymerase chain reaction. The specific cellular localization of interleukin-18 and interleukin-18 receptor expression during obstruction was assessed using dual labeling immunofluorescence staining.
Renal interleukin-18 receptor expression increased significantly in wild-type mice in response to obstruction but remained at sham operation levels in interleukin-18 receptor knockout mice. Similarly while interleukin-18 protein and gene expression were significantly increased in wild-type mice in response to obstruction, interleukin-18 levels and gene expression were significantly decreased during obstruction in knockout mice. Obstruction induced interleukin-18 and interleukin-18 receptor production were localized predominantly to tubular epithelial cells and to a lesser extent to the renal interstitium.
Results reveal that interleukin-18 stimulates a positive feedback loop via interleukin-18 receptor during renal obstruction to stimulate interleukin-18 production and gene expression. The predominant cellular source of interleukin-18 production during renal obstruction appears to be tubular epithelial cells rather than infiltrating macrophages.
白细胞介素-18 是一种促炎细胞因子，它是肿瘤坏死因子-α和β1 活性之外梗阻诱导肾小管间质性纤维化的重要介质。我们假设白细胞介素-18 通过白细胞介素-18 受体在梗阻过程中刺激正反馈回路，从而增加白细胞介素-18 基因表达和蛋白产生。
雄性 C57BL6 白细胞介素-18 受体敲除（The Jackson Laboratory，Bar Harbor，Maine）和对照野生型小鼠接受单侧输尿管梗阻或假手术，并在手术后 1 周处死。采集肾皮质组织样本，通过酶联免疫吸附试验分析白细胞介素-18 蛋白，并通过定量聚合酶链反应分析白细胞介素-18 和白细胞介素-18 受体基因表达。通过双重标记免疫荧光染色评估梗阻期间白细胞介素-18 和白细胞介素-18 受体表达的特定细胞定位。
野生型小鼠的肾白细胞介素-18 受体表达在梗阻时显著增加，但在白细胞介素-18 受体敲除小鼠中仍保持在假手术水平。同样，尽管白细胞介素-18 蛋白和基因表达在野生型小鼠对梗阻的反应中显著增加，但在敲除小鼠中，白细胞介素-18 水平和基因表达在梗阻期间显著降低。梗阻诱导的白细胞介素-18 和白细胞介素-18 受体产生主要定位于肾小管上皮细胞，其次是肾间质。
结果表明，白细胞介素-18 通过肾梗阻期间的白细胞介素-18 受体刺激正反馈回路，刺激白细胞介素-18 的产生和基因表达。在肾梗阻期间，白细胞介素-18 产生的主要细胞来源似乎是肾小管上皮细胞而不是浸润的巨噬细胞。
