NK Cell STAT3 and Virus-induced IL-6 Disease

NK 细胞 STAT3 和病毒诱导的 IL-6 疾病

• 批准号: 9352931
• 负责人: CHRISTINE A. BIRON
• 金额: $ 59.23万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-23 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9352931
• 关键词: Anti-Retroviral Agents; Antiviral Agents; Autoimmune Process; Cell physiology; Cells; Chronic Disease; Cytokine Activation; Cytomegalovirus Infections; Disease; HIV; Health; Human; Immune; Immune response; Immune system; Infection; Inflammatory; Interleukin-6; Laboratories; Licensing; Liver; Malignant Neoplasms; Mediating; Modeling; Mono-S; Morphology; Murid herpesvirus 1; Natural Killer Cells; Pathology; Pathway interactions; Play; Production; Rheumatoid Arthritis; Role; Shapes; Signal Transduction; Source; Spleen; Stat3 protein; Syndrome; Testing; Tissues; Virus; Virus Diseases; Virus Replication; Work; base; cell type; cellular targeting; clinically relevant; conditioning; cytokine; infancy; novel; novel therapeutics; protective effect; response

 DESCRIPTION (provided by applicant): Both innate cytokines and immune cells contribute to defense against viral infections. Virus is a critical part of pathology during infection. Frequentl, however, elicited immune responses rather than the agent itself cause the detrimental consequences of infection. The cytokine IL-6 is one factor that can play a role in chronic diseases such as rheumatoid arthritis (RA) and may be part of the immune reactivation inflammatory syndrome (IRIS) following successful anti-retroviral therapy (ART) in HIV-infected humans, but the mechanisms by which it leads to disease are not known. Natural killer (NK) cells of the innate immune system play important roles in direct antiviral defense and in shaping the magnitudes of other immune responses to protect against immune-mediated pathology. Different mechanisms inducing and regulating NK cell responses, as well as pathways by which NK cell-mediated effects are delivered, have been elucidated. Nevertheless, nothing is known about how NK cells respond to or regulate IL-6 production. During studies of the expression and function of the signal transducer and activator of transcription 3 (STAT3) in NK cells, this laboratory has discovered a novel, STAT3-dependent role for NK cells in protecting against IL-6-dependent disease during murine cytomegalovirus (MCMV) infection. Based on existing information and our new preliminary studies, our hypothesis is that a cascade response leading to IL-6-mediated disease is regulated (a) by cytokine induction and activation of STAT3 in NK cells, (b) to limit IL-6 production by particular cell types, (c) to in turn protect against IL-6-mediated disease. The studies planned here will test this hypothesis in three specific aims defining: (1) the NK cell functions regulated by STAT3, (2) the pathway(s) by which NK cells regulate IL-6 production, and (3) the mechanism(s) used by IL-6 to induce disease. The studies will characterize conditioning of NK cell responses to a variety of induced cytokines, and changing IL-6 effects on immune and non-immune cell subsets, in the spleen and liver as infection progresses. The work has broad clinical relevance. It promises to greatly advance understanding of the ways by which IL-6 can cause disease and to define yet another important role played by NK cells in protecting against detrimental effects during viral infections.

 描述（由申请人提供）：先天细胞因子和免疫细胞都有助于防御病毒感染，但病毒通常会引起免疫反应，而不是细胞因子本身引起感染。 -6 是在类风湿性关节炎 (RA) 等慢性疾病中发挥作用的因素之一，并且可能是成功抗逆转录病毒治疗 (ART) 后免疫再激活炎症综合征 (IRIS) 的一部分。感染艾滋病毒的人类，但其导致疾病的机制尚不清楚，先天免疫系统的自然杀伤（NK）细胞在直接抗病毒防御和塑造其他免疫反应的强度方面发挥着重要作用，以防止免疫系统的破坏。然而，在研究过程中，关于 NK 细胞如何响应或调节 IL-6 的产生尚不清楚。表达式和函数的该实验室基于 NK 细胞中信号转导器和转录激活剂 3 (STAT3) 的功能，在现有的基础上，发现了 NK 细胞在预防小鼠巨细胞病毒 (MCMV) 感染期间预防 IL-6 依赖性疾病方面的一种新的、依赖于 STAT3 的作用。根据我们的信息和新的初步研究，我们的假设是，导致 IL-6 介导的疾病的级联反应受到 (a) NK 细胞中细胞因子诱导和 STAT3 激活的调节，(b) 限制 IL-6 (c) 进而预防 IL-6 介导的疾病。这里计划的研究将在三个具体目标中检验这一假设：(1) STAT3 调节的 NK 细胞功能，(2) STAT3 调节的 NK 细胞功能。 NK 细胞调节 IL-6 产生的途径，以及 (3) IL-6 诱导疾病的机制。这些研究将表征 NK 细胞对各种诱导细胞因子的反应的调节，以及变化。 IL-6 对免疫和非免疫的影响随着感染的进展，这项工作有望极大地促进对 IL-6 引起疾病的方式的理解，并确定 NK 细胞在预防感染方面发挥的另一个重要作用。病毒感染期间的不良影响。