Altered hepatic lymphocyte subpopulations in obesity-related murine fatty livers: Potential mechanism for sensitization to liver damage
Altered hepatic lymphocyte subpopulations in obesity-related murine fatty livers: Potential mechanism for sensitization to liver damage
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DOI：
10.1002/hep.510310313
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发表时间：
2000-03-01
期刊：
影响因子：
13.5
通讯作者：
Diehl, AM
中科院分区：
文献类型：
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作者：
Guebre-Xabier, M;Yang, SQ;Diehl, AM
虽然肥胖相关的脂肪肝容易受到内毒素的损害，但涉及的机制尚不清楚，本研究的目的是确定是否可能涉及免疫启动，方法是确定脂肪肝是否类似于正常肝脏，后者已对痤疮丙酸杆菌感染的内毒素损害敏感。后者诱导IL-12和IL-18，导致CD_4+NK T细胞选择性减少，IL-4产生减少，T辅助细胞2型(Th-2)细胞因子(如IL-10)产生不足，Th-L细胞因子(如干扰素-γ)过度产生。比较了遗传性肥胖、ob/ob小鼠(肥胖相关脂肪肝的一种模型)和瘦小鼠的肝和脾淋巴细胞数量和肝脏细胞因子的产生。肥胖小鼠肝脏的CD4+NK T细胞有选择性减少。内毒素攻击后，血清IL-18水平基本升高，肝组织IL-18、IL-12基因表达水平升高。因此，脂肪肝组织中IL-18和IL-12的上调可能会降低肝脏中的CD4+NK T细胞。此外，来自脂肪肝的单个核细胞减少了黏附分子-白细胞因子抗原-1(LFA-1)的表达，这是肝脏积累CD4+NK T细胞所必需的。脂肪肝来源的单个核细胞产生的IL-4减少，与肝脏CD4+NK T细胞数量减少一致，而且内毒素治疗后，肝脏产生IL-10受到抑制，而干扰素-γ产生增强。因此，脂肪肝具有固有的免疫变化，这可能使它们容易受到内毒素和其他诱导促炎细胞因子反应的侮辱的损害。
Although obesity-related fatty livers are vulnerable to damage from endotoxin, the mechanisms involved remain obscure, The purpose of this study was to determine if immunologic priming might be involved by determining if fatty livers resemble normal livers that have been sensitized to endotoxin damage by Propionibacterium acnes infection. The latter induces interleukin (IL)-12 and -18, causing a selective reduction of CD4+NK T cells, diminished IL-4 production, deficient production of T-helper type 2 (Th-2) cytokines (e.g,, IL-10), and excessive production of Th-l cytokines (e.g,, interferon gamma [IFN-gamma]). Liver and spleen lymphocyte populations and hepatic cytokine production were compared in genetically obese, ob/ob mice (a model for obesity-related fatty liver) and lean mice. Obese mice have a selective reduction of hepatic CD4+NK T cells. Serum IL-18 is also increased basally, and the hepatic mRNA levels of IL-18 and -12 are greater after endotoxin challenge. Thus, up-regulation of IL-18 and IL-12 in fatty livers may reduce hepatic CD4+NK T cells. In addition, mononuclear cells from fatty livers have decreased expression of the adhesion molecule, leukocyte factor antigen-1 (LFA-1), which is necessary for the hepatic accumulation of CD4+NK T cells. Consistent with reduced numbers of hepatic CD4+NK T cells, mononuclear cells from fatty livers produce less IL-4, Furthermore, after endotoxin treatment, hepatic induction of IL-10 is inhibited, while that of IFN-gamma is enhanced. Thus, fatty livers have inherent immunologic alterations that may predispose them to damage from endotoxin and other insults that induce a proinflammatory cytokine response.