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: 8167438
• 负责人: KRISTEN Andrea MITCHELL
• 金额: $ 6.58万
• 依托单位: UNIVERSITY OF IDAHO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8167438
• 关键词: Affect; Aromatic Hydrocarbons; Aryl Hydrocarbon Receptor; Binding; Cell Communication; Cells; Cirrhosis; Computer Retrieval of Information on Scientific Projects Database; Developmental Process; Dioxins; Exposure to; Funding; Grant; Hepatitis; Homeostasis; Host resistance; Immune; Immune system; Institution; Ligands; Light; Liver; Liver Regeneration; Liver diseases; Lymphocyte; Lymphocyte Function; Mediating; Natural Killer Cells; Natural regeneration; Organ; Physiological Processes; Play; Production; Receptor Activation; Reperfusion Injury; Research; Research Personnel; 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; cytokine; immune function; immunoregulation; intrahepatic; liver cell proliferation; pathogen; pathogen exposure; regenerative; response; trafficking

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 免疫系统对2，3，7，8-四氯二苯并-对二恶英(TCDD)等卤代芳香烃的毒性非常敏感。TCDD和相关化合物通过与芳烃受体(AhR)结合来发挥其毒性作用，AhR是一种可溶性的配体激活的转录因子。啮齿动物暴露于TCDD可改变淋巴细胞的激活、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。大量研究表明，AhR介导的免疫系统变化最终会降低宿主对各种病原体的抵抗力，但对AhR激活对免疫系统外器官免疫调节动态平衡的影响却知之甚少。越来越多的证据表明，天然免疫系统传统上被认为是病原体暴露期间的非特异性第一道防线，在发育过程和应激反应中发挥着重要作用。在肝脏中，天然免疫系统的激活与肝硬变、重型肝炎、缺血-再灌注损伤以及再生相一致。我们以前已经证明，暴露于TCDD会抑制PH后的肝再生。在此，我们认为AhR介导的免疫功能改变有助于这种抑制。这些研究将验证一种假设，即TCDD激活AhR会加剧肝脏中NKT和NK细胞的激活，导致再生反应减弱。这一假说将在以下三个目标的背景下得到检验：1)表征AhR激活对再生肝中肝内淋巴细胞(NK和NKT细胞)增殖、募集和激活的影响；2)研究AhR激活如何改变肝再生过程中的细胞因子环境；以及3)确定AhR介导的肝再生抑制是否需要NK和NKT细胞。这些研究的结果将阐明暴露在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，这一点人们知之甚少。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在肝病治疗期间制定促进或抑制肝细胞增殖的治疗策略。免疫系统通过细胞与细胞之间的相互作用，以及细胞内的激活和抑制机制，很容易成为我们“细胞信号”的中心主题。