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Mechanisms for the administration route-dependent induction of IL-6 by carbon tetrachloride and the suppression of liver injury by IL-6

四氯化碳给药途径依赖性诱导 IL-6 及 IL-6 抑制肝损伤的机制

基本信息

批准号：
14572113
负责人：
HOJO Hiroshi
金额：
$ 1.92万
依托单位：
Showa Pharmaceutical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

项目摘要

The carbon tetrachloride-induced hepatic injury model has been used for investigating hepatitis mechanisms or for screening anti-hepatitis drugs. We have recently found that IL-6 is induced in plasma of rats by s.c. or i.p. injection of carbon tetrachloride, but not by its p.o. ingestion, and suggested that IL-6 suppresses the development of liver injury.First, the site of IL-6 production was examined Since IL-6 was detected in peritoneal exudates fluid more than in plasma after i.p. carbon tetrachloride administration, the site of IL-6 production was expected to be done in some tissues or cells in the peritoneal cavity. IL-6 mRNA was observed to be expressed more in the peritoneum, omentum, and diaphragm in the carbon tetrachloride treated rats than control. However, there was no difference in IL-6 mRNA expression of liver, spleen, and kidney between the experimental and control animals. These results suggest that IL-6 mRNA is expressed in the serosal membrane in the peritoneal cavity, when rats are treated i.p. with carbon tetrachloride.Next, inflammatory factors mediating IL-6 production were examined In the peritoneal exudate fluid, PGE_2 and histamine were increased 30 min after, and IL-1α and TNFα were increased with a peak at 1 hr after i.p. CCl_4 administration. These four factors were assayed for IL-6-indudng activity in the culture of mesothelial cells, which were separated from the intraperitoneal serous membrane by incubating with trypsin-EDTA. PGE_2, IL-1α, and TNFα except histamine tested stimulated IL-6 production in a dose-dependent manner. These results suggest that carbon tetrachloride induces PGE_2, IL-1α or TNFα in peritoneal exudates, which may be derived from peritoneal cells, and then, these factors stimulate IL-6 production in the peritoneal serous membrane.

四氯化碳诱导的肝损伤模型已被用于研究肝炎机制或筛选抗肝炎药物。我们最近发现，IL-6诱导大鼠血浆中的s.c.或腹膜内注射四氯化碳，但不是通过其口服。首先，检查IL-6产生的位点。由于腹膜内四氯化碳给药后，在腹膜渗出液中比在血浆中检测到更多的IL-6，因此预期IL-6产生的位点发生在腹膜腔中的某些组织或细胞中。四氯化碳处理组大鼠腹膜、网膜和膈肌中IL-6 mRNA表达明显高于对照组。而肝、脾、肾组织中IL-6 mRNA的表达在实验组和对照组之间无明显差异。腹腔注射CCl_4后30分钟，腹腔渗出液中PGE_2和组胺明显升高，IL-1α和TNFα也明显升高，并于1小时达高峰。用胰蛋白酶-EDTA孵育从腹膜浆膜分离的间皮细胞培养物中测定这四种因子的IL-6诱导活性。除组胺外，PGE_2、IL-1α和TNFα均呈剂量依赖性刺激IL-6产生。结果提示，四氯化碳可诱导腹膜渗出液中的PGE_2、IL-1α或TNFα，这些物质可能来源于腹膜细胞，进而刺激腹膜浆膜产生IL-6。