Kupffer cell and interleukin-12-dependent loss of natural killer T cells in hepatosteatosis.
Kupffer cell and interleukin-12-dependent loss of natural killer T cells in hepatosteatosis.
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DOI：
10.1002/hep.23292
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发表时间：
2010-01
期刊：
影响因子：
13.5
通讯作者：
Hines, Ian N.
中科院分区：
文献类型：
--
作者：
Kremer, Michael;Thomas, Emmanuel;Milton, Richard J.;Perry, Ashley W.;van Rooijen, Nico;Wheeler, Michael D.;Zacks, Steven;Fried, Michael;Rippe, Richard A.;Hines, Ian N.
肝纤维化与肿瘤坏死因子α (TNFα)和白细胞介素(IL)-12、主要T辅助细胞因子（Th） 1的表达增加以及肝NKT细胞数量减少有关。脂质积累、细胞因子表达和肝脏NKT细胞之间的关系尚不清楚。本研究旨在评估IL-12在肝脂肪变性发展中的作用及其对肝脏NKT细胞的潜在影响。雄性C57Bl/6野生型（Wt）和il -12缺陷型（il -12- / -）小鼠分别饲喂胆碱缺乏饮食（CDD） 0、10和20周。CDD导致小鼠明显的肝骨化，肝脏（而非脾脏）NKT细胞数量和功能减少，肝脏中th1型细胞因子IL-12、干扰素γ (IFNγ)和TNFα的表达增加。IL-12的缺失导致了类似的cdd诱导的肝纤维化，但保留了肝脏NKT细胞，并显著降低了肝脏IFNγ和TNFα的表达。在CDD诱导的脂肪肝中，脂多糖处理小鼠肝脏IL-12表达显著增加，Kupffer细胞（KC）缺失降低肝脏IL-12表达，恢复NKT细胞。有趣的是，与对照组小鼠的KCs相比，CDD喂养小鼠的KCs在体外激活后未能产生更多的IL-12，这表明体内的次要因素促进了IL-12的产生。最后，严重脂肪变性的人类肝脏显示出NKT和NK细胞的大量减少。肝骨化症以KC和il -12依赖的方式减少肝NKT细胞的数量。我们的研究结果表明，kc来源的IL-12在脂肪变性肝的免疫反应改变中具有关键和多功能的作用，这一过程可能在人类非酒精性脂肪性肝病中活跃。
Hepatosteatosis is associated with increased expression of tumor necrosis factor alpha (TNFα) and interleukin (IL)-12, major T helper (Th) 1 cytokines, and reduced hepatic NKT cell numbers. The relationship between lipid accumulation, cytokine expression, and hepatic NKT cells is not known. This study was conducted to assess the role of IL-12 in the development of hepatic steatosis and its potential impact on liver NKT cells. Male C57Bl/6 wild type (Wt) and IL-12-deficient (IL12−/−) mice were fed a choline deficient diet (CDD) for 0, 10 or 20 weeks. CDD led to marked hepatosteatosis, reduced hepatic but not splenic NKT cell numbers and function and increased hepatic expression of the Th1-type cytokines IL-12, interferon gamma (IFNγ) and TNFα in wt mice. Absence of IL-12 resulted in similar CDD-induced hepatosteatosis, but preserved hepatic NKT cells and significantly reduced hepatic IFNγ and TNFα expression. Treatment of CDD fed mice with lipopolysaccharide led to a significant increase in hepatic IL12 expression and Kupffer cell (KC)_depletion reduced liver IL-12 expression and restored NKT cells in CDD-induced fatty liver. Interestingly, KCs from CDD fed mice failed to produce increased quantities of IL12 upon activation in vitro when compared to similarly treated KCs from control fed mice suggesting that secondary factors in vivo promote heightened IL-12 production. Finally, human livers with severe steatosis showed a substantial decrease in NKT and NK cells. Hepatosteatosis reduces the numbers of hepatic NKT cells in a KC and IL-12-dependent manner. Our results suggest a pivotal and multi-functional role of KC-derived IL-12 in the altered immune response in steatotic liver, a process which is likely active within human non-alcoholic fatty liver disease.
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