Departments of Internal Medicine and Liver Research Institute Pathology, Seoul National University College of Medicine Department of Internal Medicine and Healthcare Research Institute, Korea.
Hepatol Res. 2011 Jan;41(1):79-86. doi: 10.1111/j.1872-034X.2010.00735.x. Epub 2010 Oct 25.
Hepatic stellate cells (HSCs) have immune regulatory functions. Mesalamine is an effective immune regulatory drug for inflammatory bowel disease. Thus, we hypothesized that mesalamine may also modulate the immune regulatory functions of HSCs. Since B7-H1 plays a crucial role in regulating T-cell apoptosis, we evaluated if mesalamine induces B7-H1 expression on HSCs, and if so, whether mesalamine attenuates autoimmune liver injury in vivo.
LX-2 cells, an immortalized human HSC cell line, and human peripheral T-cells were used in this study. B7-H1 expression on LX-2 cells following mesalamine treatment was examined by using flow cytometry. Cell viability was analyzed by MTS assay. Concanavalin-A (ConA) mice hepatitis model was used for in vivo study.
Flow cytometry showed that mesalamine treatment increased the B7-H1-expressing LX-2 cell fraction from 45.4% to 88.2%, of which increment is equivalent to that of positive control (29.9%, interferon γ-treated cells). Human T-cells incubated with LX-2 cells showed significantly less cell viability in the presence of mesalamine than cells without mesalamine treatment (P < 0.001). Histological examination revealed that hepatic necroinflammation was significantly attenuated by mesalamine pretreatment (P = 0.019), although serum levels of aminotransferases were not significantly reduced. During the 24-h period following ConA injection, 1 of 10 mice pretreated with mesalamine and 3 of 10 mice without pretreatment died.
These results demonstrate that mesalamine enhances B7-H1 expression on HSCs, and thus, induces T-cell apoptosis and attenuates autoimmune liver injury.
肝星状细胞（HSCs）具有免疫调节功能。美沙拉嗪是一种治疗炎症性肠病的有效免疫调节药物。因此，我们假设美沙拉嗪可能也调节 HSCs 的免疫调节功能。由于 B7-H1 在调节 T 细胞凋亡中起着至关重要的作用，我们评估了美沙拉嗪是否诱导 HSCs 表达 B7-H1，以及如果是这样，美沙拉嗪是否在体内减轻自身免疫性肝损伤。
本研究使用 LX-2 细胞（一种永生化的人 HSC 细胞系）和人外周 T 细胞。通过流式细胞术检测美沙拉嗪处理后 LX-2 细胞上 B7-H1 的表达。通过 MTS 测定分析细胞活力。使用伴刀豆球蛋白 A（ConA）诱导的小鼠肝炎模型进行体内研究。
流式细胞术显示，美沙拉嗪处理后，B7-H1 表达的 LX-2 细胞比例从 45.4%增加到 88.2%，增加量与阳性对照（29.9%，干扰素 γ 处理的细胞）相当。与未经美沙拉嗪处理的细胞相比，与 LX-2 细胞孵育的人 T 细胞在存在美沙拉嗪的情况下细胞活力明显降低（P < 0.001）。组织学检查显示，美沙拉嗪预处理显著减轻肝坏死性炎症（P = 0.019），尽管血清转氨酶水平没有显著降低。在 ConA 注射后的 24 小时内，10 只经美沙拉嗪预处理的小鼠中有 1 只死亡，而未经预处理的 10 只小鼠中有 3 只死亡。
这些结果表明，美沙拉嗪增强 HSCs 上的 B7-H1 表达，从而诱导 T 细胞凋亡并减轻自身免疫性肝损伤。
