Ethanol Effects on Antigen Presentation in Liver Cells

乙醇对肝细胞中抗原呈递的影响

• 批准号: 7140421
• 负责人: NATALIA ALEKSANDR OSNA
• 金额: $ 17.69万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-10 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7140421
• 关键词: JAK kinase; MHC class I antigen; SDS polyacrylamide gel electrophoresis; alcohol dehydrogenase; aminopeptidase; antigen presentation; biological signal transduction; cell membrane; cytochrome P450; cytotoxic T lymphocyte; densitometry; enzyme activity; ethanol; human tissue; immune response; immunoregulation; interferon gamma; laboratory mouse; liver cells; phosphorylation; proteasome; tissue /cell culture; toxin metabolism; western blottings

DESCRIPTION (provided by applicant): The major objective of the proposed R21 investigation is to examine the influence of ethanol and ethanol metabolism on major histocompatibility complex (MHC) class l-restricted presentation of antigenic peptides in ethanol-metabolizing liver cell lines. After activation with interferon gamma (IFNy), these peptides are cleaved by major antigen-trimming enzymes, the proteasome and leucine amino peptidase. Our previous investigations have indicated that ethanol suppresses proteasome activity in ethanol-metabolizing HepG2 cells, and that these ethanol-treated cells do not properly transduce the IFNy signal. We hypothesize that in liver cells, ethanol metabolism blocks IFNy-mediated signal transduction. This impairs IFNy-regulated induction of the immunoproteasome and of leucine amino peptidase, compromising their ability to generate peptides for antigen presentation and may alter immune response. We therefore propose the following Specific Aims: SPECIFIC AIM 1: To investigate whether ethanol or its metabolism affects the IFNy-induced cleavage of peptides for MHC class l-restricted antigen presentation in mouse recombinant HepB6 cells and in human recombinant HepG2 cells that express alcohol dehydrogenase and cytochrome P4502E1. SPECIFIC AIM 2: To determine whether ethanol exposure affects IFNy-mediated signal transduction by examining ethanol-elicited alterations in specific components of the JAK-STAT1 signal transduction pathway in mouse recombinant HepB6 cells and in human recombinant HepG2 cells. SPECIFIC AIM 3: To determine whether ethanol or its metabolism affects MHC class l-restricted antigen presentation by liver cells, using a model of the intracellular cleavage of ovalbumin (OVA) and the presentation of OVA peptide SIINFEKL-H-2Kb complex on the surface of mouse recombinant HepB6 cells. The results derived from this study will clarify the link between the effects of ethanol on antigen presentation by liver cells, altered immune response and the possible mechanisms of alcohol-related progression of viral hepatitis.

描述（由申请人提供）：所提议的 R21 研究的主要目的是检查乙醇和乙醇代谢对乙醇代谢肝细胞系中抗原肽的主要组织相容性复合体 (MHC) I 类限制性呈递的影响。用干扰素γ (IFNy) 激活后，这些肽被主要的抗原修饰酶、蛋白酶体和亮氨酸氨基肽酶裂解。我们之前的研究表明，乙醇抑制乙醇代谢 HepG2 细胞中的蛋白酶体活性，并且这些乙醇处理的细胞不能正确转导 IFNγ 信号。我们假设在肝细胞中，乙醇代谢会阻断 IFNγ 介导的信号转导。这会损害 IFNγ 调节的免疫蛋白酶体和亮氨酸氨基肽酶的诱导，损害它们生成用于抗原呈递的肽的能力，并可能改变免疫反应。因此，我们提出以下具体目标： 具体目标 1：研究乙醇或其代谢是否影响表达乙醇脱氢酶的小鼠重组 HepB6 细胞和人重组 HepG2 细胞中 IFNγ 诱导的 MHC I 类限制性抗原呈递肽裂解和细胞色素P4502E1。具体目标 2：通过检查乙醇引起的小鼠重组 HepB6 细胞和人重组 HepG2 细胞中 JAK-STAT1 信号转导途径特定成分的变化，确定乙醇暴露是否影响 IFNγ 介导的信号转导。具体目标 3：使用卵清蛋白 (OVA) 细胞内裂解和 OVA 肽 SIINFEKL-H-2Kb 复合物在表面的呈递模型，确定乙醇或其代谢是否影响肝细胞的 MHC I 类限制性抗原呈递小鼠重组 HepB6 细胞。这项研究的结果将阐明乙醇对肝细胞抗原呈递的影响、改变的免疫反应以及与酒精相关的病毒性肝炎进展的可能机制之间的联系。

项目成果

Implication of altered proteasome function in alcoholic liver injury.

蛋白酶体功能改变对酒精性肝损伤的影响。

• DOI: 10.3748/wjg.v13.i37.4931
• 发表时间: 2007
• 期刊: World journal of gastroenterology
• 影响因子: 4.3
• 作者: Osna,NataliaA;DonohueJr,Terrence-M
• 通讯作者: DonohueJr,Terrence-M

Ethanol metabolism alters major histocompatibility complex class I-restricted antigen presentation in liver cells.

• DOI: 10.1002/hep.22787
• 发表时间: 2009-04
• 期刊: HEPATOLOGY
• 影响因子: 13.5
• 作者: Osna, Natalia A.;White, Ronda L.;Thiele, Geoffrey M.;Donohue, Terrence M., Jr.
• 通讯作者: Donohue, Terrence M., Jr.