Margalit Maya, Abu Gazala Samir, Alper Ruslana, Elinav Eran, Klein Athalia, Doviner Victoria, Sherman Yoav, Thalenfeld Barbara, Engelhardt Dean, Rabbani Elazar, Ilan Yaron
Liver Unit, Department of Medicine, Hadassah University Hospital, Jerusalem, Israel.
Am J Physiol Gastrointest Liver Physiol. 2005 Nov;289(5):G917-25. doi: 10.1152/ajpgi.00105.2005. Epub 2005 Jun 23.
Concanavalin A (ConA) induces natural killer T (NKT) cell-mediated liver damage. Glucocerebroside (GC) is a naturally occurring glycolipid. Our aims were to determine the effect of GC in a murine model of ConA-induced hepatitis. Mice in groups A and B were treated with GC 2 h before and 2 h following administration of ConA, respectively; group C mice were treated with ConA; group D mice was treated with GC; group E mice did not receive any treatment. Liver damage was evaluated by serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels and liver histology. The immune effect of GC was determined by fluorescence-activated cell sorter analysis of intrahepatic and intrasplenic NKT lymphocytes, measurement of cytokine levels, and Western blot analysis for STAT 1, 4, 6, and NF-kappaB expression. The effect of GC on NKT cell proliferation was assessed in vitro. Serum AST and ALT levels were markedly reduced in GC-treated group A mice compared with nontreated group C animals, and histological damage was markedly attenuated in group A. The beneficial effect of GC was associated with a 20% decrease of intrahepatic NKT lymphocytes, significant lowering of serum IFN-gamma levels, and decreased STAT1 and STAT6 expression. In vitro administration of GC led to a 42% decrease of NKT cell proliferation in the presence of dendritic cells but not in their absence. Intraperitoneally administered radioactive GC was detected in the liver and bowel. Administration of GC led to amelioration of ConA hepatitis associated with an inhibitory effect on NKT lymphocytes. GC holds promise as a new immune-modulatory agent.
刀豆球蛋白A（ConA）可诱导自然杀伤T（NKT）细胞介导的肝损伤。葡萄糖脑苷脂（GC）是一种天然存在的糖脂。我们的目的是确定GC在ConA诱导的肝炎小鼠模型中的作用。A组和B组小鼠分别在给予ConA前2小时和后2小时用GC处理；C组小鼠用ConA处理；D组小鼠用GC处理；E组小鼠未接受任何处理。通过血清天冬氨酸氨基转移酶（AST）和丙氨酸氨基转移酶（ALT）水平以及肝脏组织学评估肝损伤。通过对肝内和脾内NKT淋巴细胞进行荧光激活细胞分选分析、细胞因子水平测定以及对STAT 1、4,、6和核因子κB表达进行蛋白质印迹分析来确定GC的免疫作用。在体外评估GC对NKT细胞增殖的影响。与未处理的C组动物相比，GC处理的A组小鼠血清AST和ALT水平明显降低，A组的组织学损伤明显减轻。GC的有益作用与肝内NKT淋巴细胞减少20%、血清干扰素-γ水平显著降低以及STAT1和STAT6表达降低有关。在有树突状细胞存在的情况下，体外给予GC导致NKT细胞增殖减少42%，而在没有树突状细胞的情况下则没有这种效果。在肝脏和肠道中检测到腹腔注射的放射性GC。给予GC可改善ConA肝炎，对NKT淋巴细胞具有抑制作用。GC有望成为一种新的免疫调节药物。
