CrmA gene expression protects mice against concanavalin-A-induced hepatitis by inhibiting IL-18 secretion and hepatocyte apoptosis
CrmA gene expression protects mice against concanavalin-A-induced hepatitis by inhibiting IL-18 secretion and hepatocyte apoptosis
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DOI：
10.1038/sj.gt.3302067
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发表时间：
2003-09-01
期刊：
影响因子：
5.1
通讯作者：
Li, XK
中科院分区：
文献类型：
--
作者：
Fujino, M;Kawasaki, M;Li, XK
激活的细胞毒性T细胞通过Fas/Fas配体和穿孔素/颗粒酶途径介导的肝细胞凋亡被认为涉及刀豆球蛋白A（ConA）诱导的肝炎模型。本研究的目的是探讨细胞因子反应调节因子A（crmA）基因是否能有效抑制刀豆蛋白A（ConA）诱导的肝细胞凋亡。我们研究了存活率，肝脏病理学，免疫组织学变化，和细胞因子的配置文件从小鼠接受重组腺病毒载体含有cre和/或crmA基因，转移到肝脏3天前ConA注射，和crmA基因nonexpression对照组。ConA注射后，小鼠肝细胞迅速凋亡，白细胞尤其是CD 11b（+）炎性细胞浸润。相比之下，表达crmA基因的小鼠的肝脏损伤显着减少。但CD 4（+）细胞的浸润不受影响。与对照组相比，治疗组小鼠的存活率显著增加至100%。此外，我们证明了白细胞介素（IL）-18在刀豆蛋白A诱导的肝炎中起着重要作用，crmA的表达显着抑制IL-18的分泌。我们的研究结果表明，crmA基因有效地抑制ConA肝炎诱导的细胞凋亡。这表明crmA用于保护免受肝炎引起的细胞损伤的潜在治疗用途。
Activated cytotoxic T-cell-mediated hepatocyte apoptosis via Fas/Fas-ligand and perforin/granzyme pathways are believed to involve the model of concanavalin A (ConA)induced hepatitis. The purpose of the present study is to investigate whether the cytokine response modifier A (crmA) gene effectively inhibits the hepatocyte apoptosis of ConA-induced hepatitis. We examined survival rates, liver pathology, immune histological changes, and cytokine profiles from mice receiving the recombinant adenovirus vectors containing cre and/or crmA genes, transferred to the liver 3 days before ConA injection, and a crmA gene nonexpression control group. Injection of ConA into mice rapidly led to massive hepatocyte apoptosis, and infiltration of leukocytes, especially CD11b(+) inflammatory cells. In contrast, liver damage was dramatically reduced in the mice that expressed the crmA gene. However, infiltration by CD4(+) cells was not affected. The survival of the mice increased significantly to 100% in the treated group versus the control group. Furthermore, we demonstrated that interleukin (IL)-18 plays an important role in ConA-induced hepatitis, and that crmA expression significantly inhibited IL-18 secretion. Our results showed that the crmA gene effectively inhibits apoptosis induced by ConA hepatitis. This indicates a potential therapeutic usage of crmA for protection from cellular damage due to hepatitis.