Isayama Fuyumi, Moore Sherri, Hines Ian N, Wheeler Michael D
Center for Alcohol Studies, University of North Carolina, Chapel Hill, North Carolina.
Department of Nutrition Science, College of Allied Health, East Carolina University, Greenville, North Carolina.
Am J Pathol. 2016 Jun;186(6):1524-36. doi: 10.1016/j.ajpath.2016.02.006. Epub 2016 Apr 18.
The role of Fas-mediated apoptosis and its effect on proinflammatory cytokine production in early alcoholic liver disease has not been addressed. Wild-type mice (C57Bl/6) or mice with a functional mutation in the Fas ligand (B6.gld) were given either high-fat control diet or ethanol diet by intragastric cannulation for 2 or 4 weeks. Liver injury, hepatic lipid accumulation, and proinflammatory cytokine production associated with chronic ethanol consumption were largely prevented in B6.gld mice compared with wild-type mice. Conversely, B6.gld mice given ethanol exhibited increases in collagen deposition, hepatic collagen gene expression, and profibrogenic cytokines (eg, transforming growth factor-β and IL-13) and alterations in matrix remodeling proteins (eg, matrix metalloproteinases and tissue inhibitor of metalloproteinases) compared with wild-type mice. Hepatic F4/80(+) macrophage populations were increased significantly in B6.gld mice compared with wild-type mice; hepatic CD3(+) cell populations were not significantly different. Importantly, a shift toward the expression of M2/Th2 cytokines (eg, IL-4 and IL-13) after ethanol exposure was observed in B6.gld mice compared with classical M1 cytokine expression in wild-type mice under similar conditions. In isolated macrophages, stimulation of Fas receptor minimally enhances lipopolysaccharide-induced M1 cytokine production and significantly limits M2 cytokine production. These data support the hypothesis that Fas-mediated signaling is important for an early ethanol-induced proinflammatory response but limits the profibrogenic response, regulating collagen production in response to chronic ethanol.
Fas介导的细胞凋亡在早期酒精性肝病中的作用及其对促炎细胞因子产生的影响尚未得到研究。野生型小鼠（C57Bl/6）或Fas配体存在功能性突变的小鼠（B6.gld）通过胃内插管给予高脂对照饮食或乙醇饮食2或4周。与野生型小鼠相比，B6.gld小鼠中与慢性乙醇摄入相关的肝损伤、肝脂质蓄积和促炎细胞因子产生在很大程度上得到了预防。相反，与野生型小鼠相比，给予乙醇的B6.gld小鼠在胶原沉积、肝胶原基因表达和促纤维化细胞因子（如转化生长因子-β和IL-13）方面有所增加，并且基质重塑蛋白（如基质金属蛋白酶和金属蛋白酶组织抑制剂）也发生了改变。与野生型小鼠相比，B6.gld小鼠肝脏中的F4/80(+)巨噬细胞群体显著增加；肝脏CD3(+)细胞群体没有显著差异。重要的是，与在相似条件下野生型小鼠中经典的M1细胞因子表达相比，在B6.gld小鼠中观察到乙醇暴露后向M2/Th2细胞因子（如IL-4和IL-13）表达的转变。在分离的巨噬细胞中，Fas受体的刺激对脂多糖诱导的M1细胞因子产生的增强作用最小，并且显著限制M2细胞因子的产生。这些数据支持了以下假设：Fas介导的信号传导对于早期乙醇诱导的促炎反应很重要，但限制了促纤维化反应，调节了对慢性乙醇的胶原产生。
