IMMUNOREGULATION OF LIVER REGENERATION BY THE ARYL HYDROCARBON RECEPTOR

芳基烃受体对肝脏再生的免疫调节

• 批准号: 8359684
• 负责人: KRISTEN Andrea MITCHELL
• 金额: $ 6.51万
• 依托单位: UNIVERSITY OF IDAHO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8359684
• 关键词: Affect; Aromatic Hydrocarbons; Aryl Hydrocarbon Receptor; Binding; Cell Communication; Cells; Cirrhosis; Developmental Process; Dioxins; Exposure to; Funding; Grant; Hepatitis; Homeostasis; Host resistance; Idaho; Immune; Immune system; Ligands; Light; Liver; Liver Regeneration; Liver diseases; Lymphocyte; Lymphocyte Function; Mediating; National Center for Research Resources; Natural Killer Cells; Natural regeneration; Organ; Physiological Processes; Play; Principal Investigator; Production; Receptor Activation; Reperfusion Injury; Research; Research Infrastructure; Resources; Rodent; Role; Signal Transduction; Source; Testing; Tetrachlorodibenzodioxin; Therapeutic; Toxic Environmental Substances; Toxic effect; United States National Institutes of Health; activating transcription factor; biological adaptation to stress; cost; cytokine; immune function; immunoregulation; intrahepatic; liver cell proliferation; pathogen; pathogen exposure; programs; regenerative; response; trafficking

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The immune system is exquisitely sensitive to toxicity resulting from exposure to halogenated aromatic hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). TCDD and related compounds exert their toxic effects by binding to the aryl hydrocarbon receptor (AhR), a soluble, ligand-activated transcription factor. Exposure of rodents to TCDD alters the activation, proliferation and trafficking of lymphocytes and modulates lymphocyte functions, including cytokine production and cytolytic activity. Numerous studies indicate that such AhR-mediated changes in the immune system culminate in decreased host resistance to a variety of pathogens, yet less is known about the ramifications of AhR activation on the immune-regulated homeostasis of organs outside of the immune system. Accumulating evidence indicates that the innate immune system, traditionally considered a non-specific, first line of defense during pathogen exposure, plays a fundamental role in developmental processes and stress responses. In the liver, activation of the innate immune system coincides with cirrhosis, fulminant hepatitis, ischemia-reperfusion injury, as well as regeneration. We have previously demonstrated that exposure to TCDD suppresses liver regeneration following PH. Herein we propose that AhR-mediated alterations in immune function contribute to this suppression. These studies will test the hypothesis that AhR activation by TCDD exacerbates the activation of NKT and NK cells in the liver, resulting in diminution of the regenerative response. This hypothesis will be tested in the context of the following three aims: 1) characterize the consequences of AhR activation on the proliferation, recruitment and activation of intrahepatic lymphocytes (NK and NKT cells) in the regenerating liver; 2) investigate how AhR activation alters the cytokine milieu during liver regeneration; and 3) determine if NK and NKT cells are required for the AhR-mediated suppression of liver regeneration. Results from these studies will shed light on how exposure to immunomodulatory environmental toxicants, such as dioxin, affect normal physiological processes in the liver, about which very little is known. Furthermore, these studies will expand our understanding of how liver regeneration is regulated by the immune system. This information may be useful in developing therapeutic strategies to promote or inhibit hepatocyte proliferation during treatment of liver disease. The immune system lends itself easily to our central theme of "Cell Signaling," both through cell-cell interactions, and through intracellular activation and suppression mechanisms.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 免疫系统对暴露于卤代芳烃（如2，3，7，8-四氯二苯并对二恶英（TCDD））所产生的毒性非常敏感。 四氯二苯并对二恶英及其相关化合物通过与芳香烃受体（AhR）结合而发挥毒性作用，而芳香烃受体是一种可溶性配体激活的转录因子。 啮齿动物暴露于TCDD会改变淋巴细胞的活化、增殖和运输，并调节淋巴细胞的功能，包括细胞因子的产生和细胞溶解活性。 许多研究表明，这种AhR介导的免疫系统的变化最终导致宿主对多种病原体的抗性降低，但对AhR激活对免疫系统外器官的免疫调节稳态的影响知之甚少。 越来越多的证据表明，先天免疫系统，传统上被认为是非特异性的，在病原体暴露期间的第一道防线，在发育过程和应激反应中发挥着重要作用。 在肝脏中，先天免疫系统的激活与肝硬化、暴发性肝炎、缺血再灌注损伤以及再生一致。 我们以前已经证明，暴露于TCDD抑制肝再生后PH。在此，我们建议，AhR介导的免疫功能的改变有助于这种抑制。 这些研究将检验TCDD激活AhR加剧肝脏中NKT和NK细胞激活，导致再生反应减弱的假设。 这一假设将在以下三个目标的背景下进行测试：1）表征AhR激活对肝内淋巴细胞增殖，募集和激活的后果（NK和NKT细胞）; 2）研究AhR活化如何改变肝再生过程中的细胞因子环境;和3）确定NK和NKT细胞是否是AhR介导的肝再生抑制所需的。 这些研究的结果将揭示暴露于免疫调节性环境毒物（如二恶英）如何影响肝脏的正常生理过程，对此知之甚少。 此外，这些研究将扩大我们对免疫系统如何调节肝脏再生的理解。 这些信息可能有助于开发治疗策略，以促进或抑制肝细胞增殖治疗肝病。免疫系统很容易通过细胞间的相互作用，以及细胞内的激活和抑制机制来实现我们的中心主题“细胞信号传导”。