Ethanol metabolism alters major histocompatibility complex class I-restricted antigen presentation in liver cells.
Ethanol metabolism alters major histocompatibility complex class I-restricted antigen presentation in liver cells.
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DOI：
10.1002/hep.22787
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发表时间：
2009-04
期刊：
影响因子：
13.5
通讯作者：
Donohue, Terrence M., Jr.
中科院分区：
文献类型：
--
作者：
Osna, Natalia A.;White, Ronda L.;Thiele, Geoffrey M.;Donohue, Terrence M., Jr.
蛋白酶体是一种主要的酶，它切割蛋白质以供抗原呈递。被切割的多肽运输到细胞表面，它们在MHC i类的背景下呈现。细胞毒性T淋巴细胞对这些复合物的识别对于消除携带“非自身”蛋白质的细胞至关重要。我们之前的研究表明，乙醇抑制了代谢乙醇的肝细胞中的蛋白酶体功能。我们假设蛋白酶体抑制减少了抗原肽的水解，从而减少了肽- mhc i类复合物在细胞表面的呈现。为了验证这一点，我们使用小鼠肝细胞细胞系（CYP2E1/ adh转染的HepB5细胞）或原代小鼠肝细胞，均来源于C57Bl/6小鼠的肝脏，其中存在卵清蛋白肽SIINFEKL与H2Kb络合。为了诱导H2Kb的表达，HepB5细胞先用干扰素γ (IFNγ)处理，然后再用乙醇处理。在这些细胞中，乙醇代谢不仅降低了蛋白酶体的活性，还降低了c延伸肽、SIINFEKL-TE的水解，以及SIINFEKL-TE递送到细胞质后测量的SIINFEKL-H2Kb复合物的呈现。乙醇的抑制作用部分归因于乙醇引起的IFNγ信号的损伤。然而，在原代肝细胞中，即使在没有IFNγ的情况下，我们也观察到乙醇暴露后蛋白酶体活性和抗原呈递的类似下降。我们得出结论，蛋白酶体的功能直接受到乙醇代谢的抑制，并通过阻止IFNγ的激活作用间接受到抑制。乙醇诱导的蛋白酶体活性降低有助于抑制肝细胞表面SIINFEKL-H2Kb的呈递。对病毒抗原的免疫反应在丙型肝炎或乙型肝炎病毒感染（分别为HCV和HBV）的发病机制中起着至关重要的作用。专业抗原呈递细胞（树突状细胞和巨噬细胞）负责启动免疫反应。HCV感染会损害这些细胞的功能。然而，当细胞毒性t淋巴细胞（ctl）克隆扩增建立后，消除感染细胞的下一个重要限制是肽- mhc I类复合物的可用性，这些复合物可被靶细胞（肝细胞）表面的ctl识别。
The proteasome is a major enzyme that cleaves proteins for antigen presentation. Cleaved peptides traffic to the cell surface, where they are presented in the context of MHC class I. Recognition of these complexes by cytotoxic T lymphocytes is crucial for elimination of cells bearing “non-self” proteins. Our previous studies revealed that ethanol suppresses proteasome function in ethanol-metabolizing liver cells. We hypothesized that proteasome suppression reduces the hydrolysis of antigenic peptides, thereby decreasing the presentation of the peptide-MHC class I-complexes on the cell surface. To test this, we used the mouse hepatocyte cell line (CYP2E1/ADH-transfected HepB5 cells) or primary mouse hepatocytes, both derived from livers of C57Bl/6 mice, which present the ovalbumin peptide, SIINFEKL, complexed with H2Kb. To induce H2Kb expression, HepB5 cells were treated with interferon gamma (IFNγ) and then exposed to ethanol. In these cells, ethanol metabolism decreased not only proteasome activity, but also hydrolysis of the C-extended peptide, SIINFEKL-TE and the presentation of SIINFEKL-H2Kb complexes measured after the delivery of SIINFEKL-TE to cytoplasm. The suppressive effects of ethanol were, in part, attributed to ethanol-elicited impairment of IFNγ signaling. However, in primary hepatocytes, even in the absence of IFNγ, we observed a similar decline in proteasome activity and antigen presentation after ethanol exposure. We conclude that proteasome function is directly suppressed by ethanol metabolism and indirectly, by preventing the activating effects of IFNγ. Ethanol-elicited reduction in proteasome activity contributes to the suppression of SIINFEKL-H2Kb presentation on the surface of liver cells. Immune response to viral antigens plays a crucial role in the pathogenesis of hepatitis C or B viral infections (HCV and HBV, respectively). Professional antigen-presenting cells (dendritic cells and macrophages) are responsible for priming the immune response. HCV infection impairs the functioning of these cells. However, when clonal expansion of cytotoxic T-lymphocytes (CTLs) is established, the next important restriction for elimination of infected cells is the availability of peptide-MHC class I complexes, which are recognized by CTLs on the surface of target cells (hepatocytes).
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影响因子：
29.4
作者：
Osna, Natalia A.;White, Ronda L.;Donohue, Terrence M., Jr.
通讯作者：
Donohue, Terrence M., Jr.
影响因子：
4.8
作者：
Saric, T;Beninga, J;Goldberg, AL
通讯作者：
Goldberg, AL
影响因子：
4.8
作者：
Bai, JX;Cederbaum, AI
通讯作者：
Cederbaum, AI
DOI：
10.1097/00000374-200202000-00018
发表时间：
2002-02-01
影响因子：
3.2
作者：
Nagy, LE;Lakshman, MR;Bearer, CF
通讯作者：
Bearer, CF
影响因子：
4.8
作者：
Liang, M;Melchior, F;Lin, X
通讯作者：
Lin, X