First Department of Surgery, Faculty of Medicine, University of Yamanashi, Yamanashi 409-3898, Japan.
J Immunol. 2011 Nov 1;187(9):4818-25. doi: 10.4049/jimmunol.1100490. Epub 2011 Sep 26.
Recent evidence suggests that IL-17A regulates neutrophil-dependent organ injury. Accordingly, the purpose of this study was to determine the role of IL-17A in neutrophil recruitment after ischemia-reperfusion (I/R) and in subsequent liver injury. Two mouse models including wild-type and IL-17A knockout mice were evaluated for I/R injury. The medial largest lobe of the liver was clamped for 90 min. In another set of experiments, recombinant mouse (rm)IL-17A homodimer or rmIL-17A/F heterodimer were administered to knockout mice before I/R, and liver injury was investigated. Isolated Kupffer cells were incubated with rmIL-17A or rmIL-17F, and production of TNF-α was measured. Studies evaluating the extent of liver injury as measured by serum transaminase levels demonstrated similar levels in the acute phase (6 h) in these two models. In contrast, in the subacute phase (20 h) after I/R, both serum transaminase levels and percent of hepatic necrosis were significantly reduced in the knockout mice compared with the wild-type mice. This reduction in liver injury seen in the knockout mice was associated with suppression of chemokine and adhesion molecule expression and reduction in infiltration of neutrophils into the liver. Administration of rmIL-17A homodimer, but not IL-17A/F heterodimer, increased liver injury in the subacute phase of I/R in KO mice. TNF-α production by isolated Kupffer cells increased significantly in the cells incubated with rmIL-17A compared with rmIL-17F. These results indicate that IL-17A is a key regulator in initiating neutrophil-induced inflammatory responses and hepatic injury in the subacute phase after reperfusion.
最近的证据表明，IL-17A 调节中性粒细胞依赖性器官损伤。因此，本研究的目的是确定 IL-17A 在缺血再灌注（I/R）后中性粒细胞募集中的作用以及随后的肝损伤。评估了包括野生型和 IL-17A 敲除小鼠在内的两种小鼠模型的 I/R 损伤。肝脏的最大中叶夹闭 90 分钟。在另一组实验中，在 I/R 前将重组小鼠（rm）IL-17A 同型二聚体或 rmIL-17A/F 异源二聚体给予敲除小鼠，并研究肝损伤。分离的枯否细胞用 rmIL-17A 或 rmIL-17F 孵育，并测量 TNF-α的产生。评估血清转氨酶水平测量的肝损伤程度的研究表明，在这两种模型的急性期（6 小时），水平相似。相比之下，在 I/R 后的亚急性期（20 小时），与野生型小鼠相比，敲除小鼠的血清转氨酶水平和肝坏死百分比均显著降低。与野生型小鼠相比，敲除小鼠中观察到的肝损伤减少与趋化因子和粘附分子表达的抑制以及中性粒细胞浸润到肝脏的减少有关。rmIL-17A 同型二聚体的给药，但不是 IL-17A/F 异源二聚体，增加了 I/R 后亚急性期 KO 小鼠的肝损伤。与 rmIL-17F 相比，用 rmIL-17A 孵育的分离枯否细胞中 TNF-α的产生显著增加。这些结果表明，IL-17A 是引发再灌注后亚急性期中性粒细胞诱导的炎症反应和肝损伤的关键调节剂。
