Department of Immunology, Mie University Graduate School of Medicine, Tsu, Mie, Japan.
J Thromb Haemost. 2015 Jan;13(1):142-54. doi: 10.1111/jth.12789. Epub 2014 Dec 11.
Alcohol consumption is a major cause of liver injury but the mechanisms are not completely understood. Protein S (PS) is an anticoagulant glycoprotein with multiple functions. The role of PS in liver injury is unknown.
This study investigated the role of PS in acute alcoholic hepatitis.
A mouse overexpressing human PS (hPS-TG) was generated in which acute hepatitis was induced by intraperitoneal injection of ethanol.
The levels of serum liver enzymes and liver tissue inflammatory cytokines and the degree of hepatic steatosis were significantly increased in hPS-TG mice treated with ethanol compared with ethanol-treated wild type (WT) mice. Cell expansion, activation and inhibition of apoptosis were significantly augmented in natural killer T (NKT) cells from hPS-TG mice compared with WT mice. Liver mononuclear cells from hPS-TG mice express higher levels of inflammatory cytokines than those from WT mice after stimulation with a specific stimulant of NKT cells in vitro. In a co-culture system of hepatocytes and NKT cells, the effects of PS on ethanol-mediated cell injury were suppressed by a CD1d neutralizing antibody. Alcoholic liver injury was significantly improved in mice pre-treated with PS siRNA and anti-protein S antibody compared with control mice. Patients with alcoholic hepatitis showed significantly increased plasma PS levels and enhanced liver expression of PS and CD1d compared with controls.
The results of this study suggest that PS exacerbates acute alcoholic hepatitis by inhibiting apoptosis of activated NKT cells.
饮酒是导致肝损伤的一个主要原因，但具体机制尚不完全清楚。蛋白 S（PS）是一种具有多种功能的抗凝糖蛋白。PS 在肝损伤中的作用尚不清楚。
本研究旨在探讨 PS 在急性酒精性肝炎中的作用。
构建了人 PS 过表达（hPS-TG）小鼠，通过腹腔注射乙醇诱导急性肝炎。
与乙醇处理的野生型（WT）小鼠相比，hPS-TG 小鼠的血清肝酶水平、肝组织炎症细胞因子水平和肝脂肪变性程度显著升高。与 WT 小鼠相比，hPS-TG 小鼠的自然杀伤 T（NKT）细胞的细胞扩增、激活和凋亡抑制显著增强。与 WT 小鼠相比，hPS-TG 小鼠的肝单核细胞在体外经 NKT 细胞特异性刺激后表达更高水平的炎症细胞因子。在肝细胞和 NKT 细胞共培养系统中，CD1d 中和抗体抑制了 PS 对乙醇介导的细胞损伤的作用。与对照组相比，用 PS siRNA 和抗蛋白 S 抗体预处理的小鼠的酒精性肝损伤明显改善。与对照组相比，酒精性肝炎患者的血浆 PS 水平显著升高，PS 和 CD1d 的肝表达增强。
本研究结果提示 PS 通过抑制激活的 NKT 细胞凋亡而加重急性酒精性肝炎。
