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，四氯化碳皮下注射或腹腔注射可诱导大鼠血浆中IL-6的表达，而非直接摄入，提示IL-6可抑制肝损伤的发生。由于四氯化碳给药后腹腔渗出液中IL-6的含量高于血浆中IL-6的含量，因此推测IL-6的产生部位可能在腹腔的某些组织或细胞中。观察到四氯化碳处理大鼠腹膜、网膜和膈膜中IL-6 mRNA的表达高于对照组。而肝、脾、肾组织中IL-6 mRNA的表达在实验动物和对照动物中均无差异。这些结果表明，四氯化碳灌胃后，大鼠腹腔浆膜中IL-6 mRNA有表达。在腹腔渗出液中，PGE_2和组胺升高，IL-1α和TNFα升高，并在给药后1小时达到峰值。用胰蛋白酶- edta孵育从腹膜内分离的间皮细胞，测定这四个因素在培养中包括il -6在内的活性。除组胺外，PGE_2、IL-1α和TNFα刺激IL-6产生呈剂量依赖性。提示四氯化碳诱导腹腔渗出液中PGE_2、IL-1α或TNFα的产生，这些因子可能来源于腹腔细胞，进而刺激腹腔浆膜中IL-6的产生。

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.