Department of Pathology, Harbor-UCLA Medical Center, 1000 W. Carson St., Torrance, CA 90509, USA.
Exp Mol Pathol. 2011 Jun;90(3):239-43. doi: 10.1016/j.yexmp.2011.01.005. Epub 2011 Jan 25.
Toll-like receptors (TLR) play a role in mediating the proinflammatory response, fibrogenesis and carcinogenesis in chronic liver diseases such as alcoholic liver disease, non-alcoholic liver disease, hepatitis C and hepatocellular carcinoma. This is true in experimental models of these diseases. For this reason, we investigated the TLR proinflammatory response in the chronic intragastric tube feeding rat model of alcohol liver disease. The methyl donor S-adenosylmethionine was also fed to prevent the gene expression changes induced by ethanol. Ethanol feeding tended to increase the up regulation of the gene expression of TLR2 and TLR4. SAMe feeding prevented this. TLR4 and MyD88 protein levels were significantly increased by ethanol and this was prevented by SAMe. This is the first report where ethanol feeding induced TLR2 and SAMe prevented the induction by ethanol. CD34, FOS, interferon responsive factor 1 (IRF-1), Jun, TLR 1,2,3,4,6 and 7 and Traf-6 were found to be up regulated as seen by microarray analysis where rats were sacrificed at high blood alcohol levels compared to pair fed controls. Il-6, IL-10 and IFNγ were also up regulated by high blood levels of ethanol. The gene expression of CD14, MyD88 and TNFR1SF1 were not up regulated by ethanol but were down regulated by SAMe. The gene expression of IL-1R1 and IRF1 tended to be up regulated by ethanol and this was prevented by feeding SAMe. The results suggest that SAMe, fed chronically prevents the activation of TLR pathways caused by ethanol. In this way the proinflammatory response, fibrogenesis, cirrhosis and hepatocellular carcinoma formation due to alcohol liver disease could be prevented by SAMe.
Toll 样受体 (TLR) 在介导慢性肝病中的促炎反应、纤维化和癌变方面发挥作用，如酒精性肝病、非酒精性肝病、丙型肝炎和肝细胞癌。在这些疾病的实验模型中确实如此。出于这个原因，我们研究了慢性胃内管饲酒精性肝病大鼠模型中的 TLR 促炎反应。还给予甲基供体 S-腺苷甲硫氨酸 (SAMe) 以预防乙醇诱导的基因表达变化。乙醇喂养倾向于增加 TLR2 和 TLR4 的基因表达上调。SAMe 喂养可预防这种情况。乙醇显著增加 TLR4 和 MyD88 蛋白水平，SAMe 可预防这种情况。这是首次报道乙醇喂养诱导 TLR2 和 SAMe 可预防乙醇诱导的情况。通过微阵列分析发现 CD34、FOS、干扰素反应因子 1 (IRF-1)、Jun、TLR1、2、3、4、6 和 7 和 Traf-6 上调，与高血酒精水平相比，高血酒精水平下大鼠被处死与配对喂养的对照相比。IL-6、IL-10 和 IFNγ 也被高血乙醇上调。CD14、MyD88 和 TNFR1SF1 的基因表达不受乙醇上调，但受 SAMe 下调。IL-1R1 和 IRF1 的基因表达受乙醇上调的趋势，这被 SAMe 喂养所阻止。结果表明，SAMe 慢性给药可预防乙醇引起的 TLR 途径激活。通过这种方式，SAMe 可预防酒精性肝病引起的促炎反应、纤维化、肝硬化和肝细胞癌形成。
