Department of Pharmacology & Toxicology, Center for Integrative Toxicology, Michigan State University, East Lansing, Michigan 48824.
Toxicol Sci. 2013 Nov;136(1):72-85. doi: 10.1093/toxsci/kft174. Epub 2013 Aug 22.
For many liver diseases, including viral and autoimmune hepatitis, immune cells play an important role in the development and progression of liver injury. Concanavalin A (Con A) administration to rodents has been used as a model of immune-mediated liver injury resembling human autoimmune hepatitis. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) has been demonstrated to alter the development of immune-mediated diseases. Mice pretreated with TCDD developed exacerbated liver injury in response to administration of a mild dose (6 mg/kg) of Con A. In the present study, we tested the hypothesis that TCDD pretreatment exacerbates Con A-induced liver injury by enhancing the activation and recruitment of accessory cell types including neutrophils, macrophages, and natural killer (NK) cells. Mice were treated with 0, 0.3, 3, or 30 μg/kg TCDD and 4 days later with Con A or saline. TCDD pretreatment with doses of 3 and 30 μg/kg significantly increased liver injury from Con A administration. The plasma concentrations of neutrophil chemokines were significantly increased in TCDD-pretreated mice after Con A administration. NKT cell-deficient (CD1d KO) mice were used to examine whether NKT cells were required for TCDD/Con A-induced liver injury. CD1d KO mice were completely protected from liver injury induced by treatment with Con A alone, whereas the injury from TCDD/Con A treatment was reduced but not eliminated. However, T-cell deficient (RAG1 KO) mice were protected from liver injury induced by Con A irrespective of pretreatment with TCDD. TCDD/Con A treatment increased the percentage of NK cells expressing the activation marker CD69. Depletion of NK cells prior to treatment resulted in significant reductions in plasma interferon-γ and liver injury from TCDD/Con A treatment. In summary, exposure to TCDD exacerbated the immune-mediated liver injury induced by Con A, and our findings suggest that NK cells play a critical role in this response.
对于许多肝脏疾病，包括病毒性和自身免疫性肝炎，免疫细胞在肝损伤的发展和进展中起着重要作用。将刀豆球蛋白 A（Con A）施用于啮齿动物已被用作类似于人类自身免疫性肝炎的免疫介导的肝损伤模型。二恶英（TCDD）已被证明可改变免疫介导的疾病的发展。用 TCDD 预处理的小鼠在用轻度剂量（6mg/kg）Con A 给药时会发展出更严重的肝损伤。在本研究中，我们检验了 TCDD 预处理通过增强辅助细胞类型（包括中性粒细胞、巨噬细胞和自然杀伤（NK）细胞）的激活和募集来加剧 Con A 诱导的肝损伤的假设。用 0、0.3、3 或 30μg/kg TCDD 处理小鼠，4 天后用 Con A 或盐水处理。用 3 和 30μg/kg TCDD 预处理显著增加了 Con A 给药后的肝损伤。在用 Con A 预处理的 TCDD 预处理小鼠中，中性粒细胞趋化因子的血浆浓度显着增加。使用 NKT 细胞缺陷型（CD1d KO）小鼠来检查 NKT 细胞是否是 TCDD/Con A 诱导的肝损伤所必需的。CD1d KO 小鼠完全免受单独用 Con A 诱导的肝损伤的影响，而 TCDD/Con A 处理引起的损伤减少但未消除。然而，T 细胞缺陷型（RAG1 KO）小鼠无论是否用 TCDD 预处理均免受 Con A 诱导的肝损伤的影响。TCDD/Con A 处理增加了表达激活标记物 CD69 的 NK 细胞的百分比。在用 TCDD/Con A 处理前耗尽 NK 细胞会导致血浆干扰素-γ和肝损伤显著减少。总之，接触 TCDD 加剧了 Con A 诱导的免疫介导的肝损伤，我们的发现表明 NK 细胞在这种反应中起关键作用。
