Critical role of interleukin-17/interleukin-17 receptor axis in mediating Con A-induced hepatitis
Critical role of interleukin-17/interleukin-17 receptor axis in mediating Con A-induced hepatitis
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IL-17/IL-17受体轴在介导Con A诱导的肝炎中的关键作用
DOI：
10.1038/icb.2011.59
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发表时间：
2012-04-01
影响因子：
4
通讯作者：
Chu, Yiwei
中科院分区：
文献类型：
--
作者：
Yan, Shu;Wang, Luman;Chu, Yiwei
伴刀豆球蛋白A（ConA）诱导的肝炎被认为是一种T细胞介导的疾病，具有肝细胞的主动破坏。白细胞介素（IL）-17是主要由CD 4（+）T细胞产生的细胞因子。然而，IL-17/IL-17受体（IL-17/IL-17 R）介导的反应是否参与T细胞介导的Con A诱导的肝损伤仍不清楚。在这项研究中，我们发现，IL-17的表达是高度升高的肝组织在Con A诱导的肝炎。IL-17水平升高与丙氨酸氨基转移酶和组织学检测所反映的肝损伤程度以及肿瘤坏死因子（TNF）-α和IL-6的分泌相关。IL-17的阻断显著改善Con A诱导的肝炎，而IL-17的过表达全身性地导致小鼠肝细胞大量坏死。此外，IL-17 R免疫球蛋白G1融合蛋白的过表达显著减弱急性Con A治疗后的肝脏炎症。还观察到库普弗细胞上IL-17 R的高表达沿着包括TNF-α和IL-6在内的细胞因子的产生。氯化钆抑制枯否细胞完全防止Con A诱导的肝损伤和细胞因子释放。最后，与对照组相比，ConA注射小鼠中表达IL-17的CD 4（+）T细胞和自然杀伤T细胞显著增加。总之，我们的研究结果表明，IL-17 R信号转导是关键参与的发病机制，在刀豆蛋白A诱导的肝炎，和IL-17/IL-17 R信号通路的阻断可能代表了一种新的治疗干预人类自身免疫相关性肝炎。Immunology and Cell Biology（2012）90，421-428; doi：10.1038/icb.2011.59; 2011年6月21日在线发表
Concanavalin A (Con A)-induced hepatitis is thought to be a T-cell-mediated disease with active destruction of liver cells. Interleukin (IL)-17 is a cytokine produced principally by CD4(+) T cells. However, whether IL-17/IL-17 receptor (IL-17/IL-17R)-mediated responses are involved in T-cell-mediated Con A-induced liver injury remains unclear. In this study, we found that IL-17 expression was highly elevated in liver tissues during Con A-induced hepatitis. The increased levels of IL-17 were paralleled with the severity of liver injury reflected by Alanine aminotransaminase and histological assay as well as the secretion of tumor necrosis factor (TNF)-alpha and IL-6. Blockage of IL-17 significantly ameliorated Con A-induced hepatitis, while overexpression of IL-17 systemically resulted in massive hepatocyte necrosis in mice. Furthermore, overexpression of an IL-17R immunoglobulin G1 fusion protein significantly attenuated liver inflammation after acute Con A treatment. High expression of IL-17R on Kupffer cells was also observed along with the production of cytokines including TNF-alpha and IL-6. Inhibition of Kupffer cells by gadolinium chloride completely prevented Con A-induced liver injury and cytokine release. Finally, IL-17-expressing CD4(+) T and natural killer T cells were greatly increased in Con A-injected mice compared with that in controls. Overall, our results indicate that IL-17R signaling is critically involved in the pathogenesis in Con A-induced hepatitis, and blockade of IL-17/IL-17R signaling pathway may represent a novel therapeutic intervention in human autoimmune-related hepatitis. Immunology and Cell Biology (2012) 90, 421-428; doi:10.1038/icb.2011.59; published online 21 June 2011