Maladaptive role of IL-6 in ischemic acute renal failure
Maladaptive role of IL-6 in ischemic acute renal failure
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DOI：
10.1681/asn.2003090757
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发表时间：
2005-11-01
影响因子：
13.6
通讯作者：
Lu, CY
中科院分区：
文献类型：
--
作者：
Kielar, ML;John, R;Lu, CY
探讨IL-6在小鼠缺血性急性肾功能衰竭中的作用。夹闭肾蒂17min，于再灌流后不同时间取材。我们发现小鼠缺血性肾损伤后血清IL-6水平升高。这种增加与缺血侧肾脏中IL-6mRNA的增加有关，而与对侧肾脏或肝脏中的IL-6mRNA的增加无关。IL-6产生高峰出现在4~8h，24 h降至基线水平，需要肾脏再灌注才能产生。原位杂交和免疫组织化学显示巨噬细胞在再灌流后数小时内可见巨噬细胞渗入外髓血管束附近区域，巨噬细胞可产生IL-6mRNA。为了了解巨噬细胞是如何被刺激产生IL-6的，我们建立了S3近端肾小管上皮细胞受活性氧损伤的体外模型。这些受损细胞在体外释放分子，激活巨噬细胞产生IL-6。在肾脏缺血时产生的IL-6是不适应的，因为转基因的IL-6基因敲除可以改善血清肌酐和组织学测量的肾脏损伤。对IL-6基因敲除小鼠进行致死性照射，并用野生型IL-6细胞重建骨髓。这种骨髓移植消除了转基因IL-6基因敲除的保护作用。结论：巨噬细胞渗入外髓血管束区，产生IL-6，而IL-6加重了缺血性急性肾功能衰竭。
The role of IL-6 was investigated in murine ischemic acute renal failure. The renal pedicles were clamped for 17 min, and the mice were studied at various times after reperfusion. We found that serum IL-6 increased after murine ischemic renal injury. This increase was associated with increased IL-6 mRNA in the ischemic kidney but not in the contralateral kidney or the liver. Maximal IL-6 production occurred at 4 to 8 h and decreased to baseline by 24 h. Reperfusion of the kidney was required for IL-6 production. In situ hybridization and immunohistochemistry showed that macro phages infiltrated areas adjacent to the vascular bundles in the outer medulla within hours of reperfusion and showed that these macrophages produced IL-6 mRNA. For understanding how macrophages were stimulated to produce IL-6, an in vitro model in which S3 proximal tubular cells were injured by reactive oxygen species was set up. These injured cells released molecules that activated macrophages to produce IL-6 in vitro. IL-6 that was produced in response to renal ischemia was maladaptive because transgenic knockout of IL-6 ameliorated renal injury as measured by serum creatinine and histology. IL-6 transgenic knockout mice were lethally irradiated, and their bone marrow was reconstituted with wild-type IL-6 cells. Such bone marrow transfers abolished the protective effects of transgenic IL-6 knockout. It is concluded that macrophages infiltrate the area of the vascular bundles of the outer medulla, these macrophages produce IL-6, and this IL-6 exacerbates ischemic murine acute renal failure.