Interleukin 18 causes hepatic ischemia/reperfusion injury by suppressing anti-inflammatory cytokine expression in mice
Interleukin 18 causes hepatic ischemia/reperfusion injury by suppressing anti-inflammatory cytokine expression in mice
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DOI：
10.1002/hep.20117
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发表时间：
2004-03-01
期刊：
影响因子：
13.5
通讯作者：
Miyazaki, M
中科院分区：
文献类型：
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作者：
Takeuchi, D;Yoshidome, H;Miyazaki, M
肝脏缺血/再灌注损伤是临床上的重要问题。虽然初始事件和随后的嗜肝细胞依赖性损伤的机制有所了解，但对内源性肝保护作用对这种损伤的调节知之甚少。白细胞介素12（IL-12）在这种损伤的诱导中起作用，但白细胞介素18（IL-18）的参与尚未阐明。使用小鼠模型的部分肝缺血和随后的再灌注，目前的研究的目的是确定是否IL-18在肝缺血/再灌注过程中上调，并确定内源性IL-18在炎症性肝缺血/再灌注损伤的发展和调节中的作用。肝IL-18表达在再灌注后18 h上调。肝缺血再灌注诱导的核因子-κ B（NF-κ B）和激活蛋白1（AP-1）激活，如通过电泳迁移率变动测定所定义的，并引起肝中性粒细胞募集、凋亡、肝细胞损伤和肝水肿的显著增加，如通过肝髓过氧化物酶含量、末端脱氧核苷酸转移酶介导的脱氧尿苷三磷酸生物素缺口末端标记（TUNEL）染色所定义的，血清氨基转移酶水平和肝脏湿干重比。在用IL-18中和抗体治疗的小鼠中，缺血/再灌注诱导的CXC趋化因子表达增加、NF-κ B和AP-1活化以及细胞凋亡大大减少。此外，在IL-18的阻断下，抗炎性细胞因子如IL-4和IL-10大大上调。在IL-18的阻断下，信号转导和转录激活因子6（STAT 6）被显著激活。这些条件还导致肝脏中性粒细胞隔离和肝损伤显著减少。总之，数据表明，IL-18是通过抑制抗炎细胞因子表达来促进嗜中性粒细胞依赖性肝缺血/再灌注损伤所必需的。
Hepatic ischemia/reperfusion injury is a clinically important problem. While the mechanisms of the initial event and subsequent neutrophil-dependent injury are somewhat understood, little is known about the regulation of endogenous hepatoprotective effects on this injury. Interleukin 12 (IL-12) plays a role in the induction of this injury, but involvement of interleukin 18 (IL-18) has not been clarified. Using a murine model of partial hepatic ischemia and subsequent reperfusion, the aim of the current study was to determine whether IL-18 is up-regulated during hepatic ischemia/reperfusion and to determine the role of endogenous IL-18 in the development and regulation of inflammatory hepatic ischemia/reperfusion injury. Hepatic IL-18 expression was up-regulated from I to 8 hours after reperfusion. Hepatic ischemia/reperfusion induced nuclear factor-kappaB (NF-kappaB) and activator protein 1 (AP-1) activation, as defined by electrophoretic mobility shift assay, and caused significant increases in liver neutrophil recruitment, apoptosis, hepatocellular injury, and liver edema as defined by liver myeloperoxidase content, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate biotin nick end-labeling (TUNEL) staining, serum aminotransferase levels, and liver wet-to-dry weight ratios. In mice treated with neutralizing antibody to IL-18, ischemia/reperfusion-induced increases in CXC chemokine expression, activation of NF-kappaB and AP-1, and apoptosis were greatly reduced. Furthermore, under blockade of IL-18, anti-inflammatory cytokines such as IL-4 and IL-10 were greatly up-regulated. Signal transducer and activator of transcription 6 (STAT6) was significantly activated under blockade of IL-18. These conditions also caused significant reduction in liver neutrophil sequestration and liver injury. In conclusion, the data suggest that IL-18 is required for facilitating neutrophil-dependent hepatic ischemia/reperfusion injury through suppressing anti-inflammatory cytokine expression.