Ethanol Effects on NK Cell Responses

乙醇对 NK 细胞反应的影响

基本信息

批准号：
7990054
负责人：
THAIS P. SALAZAR-MATHER
金额：
$ 20.25万
依托单位：
BROWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-10 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7990054
关键词：
Activated Natural Killer Cell Address Affect Alcohol abuse Alcohol consumption Alcohols Biological Models Cell Communication Cell physiology Chemicals Chronic Consumption Cytomegalovirus Infections Dendritic Cells Dendritic cell activation Development Equilibrium Ethanol Exposure to Frequencies Growth Heavy Drinking Immune Immune response Immunity Immunosuppression Impairment Incidence Infection Intake Interferons Interleukin-12 Interleukins Lead Liver Malignant Neoplasms Mediating Mediator of activation protein Mind Molecular Murid herpesvirus 1 NK Cell Activation Natural Killer Cells Organ Patients Phosphotransferases Play Poly I-C Production Regulation Relative (related person)Research Risk Role Severities Signal Pathway Signal Transduction Source Spleen TLR7 gene Testing Therapeutic Treatment Protocols Viral Virus Virus Diseases alcohol effect alcohol exposure anticancer treatment base chronic alcohol ingestion cytokine cytotoxicity design immune function in vivo innovation killings novel pathogen problem drinker public health relevance research study response trafficking transcription factor tumor

项目摘要

DESCRIPTION (provided by applicant): Excessive ethanol (EtOH) consumption impairs immune function, evident in the increased incidence and severity of certain cancers and viral infections seen in alcoholic patients; however its mechanistic role in immunosuppression is poorly understood. Because natural killer (NK) cells play a vital role in tumor surveillance and in defense against virus infections, the overall objective of this proposal is to identify the underlying in vivo mechanisms by which chronic EtOH inhibits NK cell responses. This will be accomplished under conditions of murine cytomegalovirus (MCMV) infection; a well-established model system used to study NK cell function. NK cells are quickly activated by cytokines induced in response to MCMV infection. Importantly, there is evidence that cytokine production is profoundly altered by exposure to EtOH. With this in mind, the central hypothesis of the proposed research is that chronic ethanol consumption modulates the cytokine balance that contributes to the regulation of NK cell responses. This hypothesis is based on the following observations. First, EtOH inhibits cytokines that modulate two NK cell effector functions used in defense against viral pathogens and tumors: cytotoxicity (killing) and cytokine production. Specifically, EtOH inhibits polyinosinic-polycytidylic acid (poly-I:C)-induced NK cell cytotoxicity. Poly-I:C is a chemical inducer of type 1 interferons (IFN-1/2), which activate NK cell cytotolytic effectors during MCMV infection. Second, EtOH exposure affects the release of interleukin-12, a cytokine that supports NK cell production of the regulatory cytokine IFN-3 and cytotoxicity. Third, dendritic cells, which are important sources of IFN-1/2 and IL-12, are sensitive to EtOH exposure. Based on these observations, we propose to address how EtOH-altered cytokine function impact NK cell responses to MCMV infection. It is hypothesized that chronic EtOH intake suppresses production of IFN-1/2 and IL-12 from pDC subsets, and such suppression results from modulations in the intracellular signaling pathways involved in pDC activation. In Aim 1, we will test the hypothesis by evaluating the effects of chronic EtOH on cytokine production, the expression of intermediate mediators in the TLR7/9- MyD88 signaling pathway, and the functional response of the downstream transcription factors IRF-7 and NFkB in pDC subsets. Increasing evidence supports the idea that pDC-derived cytokines are essential in initiating NK cell responses. Therefore, it is hypothesized that the suppressive effects of chronic EtOH on NK cell responses result from impaired production of cytokines in pDC subsets. In Aim 2, we will test the hypothesis by evaluating the effects of chronic EtOH on NK cell trafficking and delivery of effector function, and on pDC and NK cell interactions. The studies will elucidate novel information on the molecular mechanisms underlying cytokine dysregulation associated with chronic alcohol abuse. Identification of such mechanisms should prove valuable in understanding suppression of immune responses associated with NK cells and may have important translational implications for the development of potential therapeutics for alcoholic patients. PUBLIC HEALTH RELEVANCE: There is substantial evidence that alcohol consumption increases the risk of developing cancers of various organs. Excessive alcohol consumption also impairs immune function, evident in the increased frequency and severity of infections seen in alcoholic patients. Because NK cells promote tumor surveillance and can inhibit the growth and spread of certain cancers, understanding the mechanisms that promote inhibition of NK cell activity under conditions of alcohol exposure will have significant implications regarding efficacies of anticancer treatment protocols, and will address a research objective of this announcement.

描述（由申请人提供）：过量摄入乙醇 (EtOH) 会损害免疫功能，这在酗酒患者中某些癌症和病毒感染的发病率和严重程度增加中显而易见；然而，人们对它在免疫抑制中的机制作用知之甚少。由于自然杀伤 (NK) 细胞在肿瘤监测和防御病毒感染中发挥着至关重要的作用，因此该提案的总体目标是确定慢性乙醇抑制 NK 细胞反应的潜在体内机制。这将在鼠巨细胞病毒（MCMV）感染的条件下完成；用于研究 NK 细胞功能的完善模型系统。 NK 细胞会被 MCMV 感染诱导的细胞因子快速激活。重要的是，有证据表明接触乙醇会极大地改变细胞因子的产生。考虑到这一点，本研究的中心假设是，长期乙醇消耗会调节细胞因子平衡，从而有助于调节 NK 细胞反应。该假设基于以下观察。首先，EtOH 抑制调节用于防御病毒病原体和肿瘤的两种 NK 细胞效应功能的细胞因子：细胞毒性（杀伤）和细胞因子的产生。具体来说，EtOH 可抑制聚肌苷-聚胞苷酸 (poly-I:C) 诱导的 NK 细胞毒性。 Poly-I:C 是 1 型干扰素 (IFN-1/2) 的化学诱导剂，可在 MCMV 感染期间激活 NK 细胞溶细胞效应器。其次，EtOH 暴露会影响白细胞介素 12 的释放，白细胞介素 12 是一种支持 NK 细胞产生调节性细胞因子 IFN-3 和细胞毒性的细胞因子。第三，树突状细胞是 IFN-1/2 和 IL-12 的重要来源，对 EtOH 暴露敏感。基于这些观察，我们建议解决 EtOH 改变的细胞因子功能如何影响 NK 细胞对 MCMV 感染的反应。据推测，长期摄入 EtOH 会抑制 pDC 亚群产生 IFN-1/2 和 IL-12，这种抑制是由于参与 pDC 激活的细胞内信号通路的调节所致。在目标 1 中，我们将通过评估慢性 EtOH 对细胞因子产生的影响、TLR7/9-MyD88 信号通路中中间介质的表达以及下游转录因子 IRF-7 和 NFkB 的功能反应来检验该假设。 pDC 子集。越来越多的证据支持这样的观点：pDC 衍生的细胞因子对于启动 NK 细胞反应至关重要。因此，推测慢性乙醇对 NK 细胞反应的抑制作用是由于 pDC 亚群中细胞因子的产生受损所致。在目标 2 中，我们将通过评估慢性 EtOH 对 NK 细胞运输和效应功能传递以及 pDC 和 NK 细胞相互作用的影响来检验这一假设。这些研究将阐明与慢性酒精滥用相关的细胞因子失调的分子机制的新信息。此类机制的鉴定对于理解与 NK 细胞相关的免疫反应的抑制应该是有价值的，并且可能对酒精患者潜在疗法的开发具有重要的转化意义。公共卫生相关性：有大量证据表明饮酒会增加患各种器官癌症的风险。过量饮酒也会损害免疫功能，酗酒患者感染的频率和严重程度增加就很明显。由于 NK 细胞促进肿瘤监视并可以抑制某些癌症的生长和扩散，因此了解在酒精暴露条件下促进抑制 NK 细胞活性的机制将对抗癌治疗方案的功效产生重大影响，并将解决以下研究目标：本公告。