Tp12-dependent IFN-g production: contribution to host defense and autoimmunity

Tp12 依赖性 IFN-g 产生：对宿主防御和自身免疫的贡献

基本信息

批准号：
7135159
负责人：
Wendy T Watford
金额：
$ 16.2万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7135159
关键词：
Antibodies Antigen Presentation Area Autoimmune Diseases Autoimmunity B-Lymphocytes Biochemical Biochemical Pathway Biological Biological Assay CD4 Positive T Lymphocytes Cell Differentiation process Cell secretion Cellular Immunity Collaborations Communicable Diseases Cytokine Receptors Data Defect Development Diabetes Mellitus Disease Drug Design Effector Cell Event Gene Expression Genes Genetic Transcription Goals Homeostasis Host Defense Human Immune response Immunity Immunoblotting Immunoglobulin Class Switching Infection Inflammatory Inflammatory Bowel Diseases Interferon Type II Interferons Interleukin-12 Interleukins Intervention Knockout Mice Knowledge Link Lymphoid MAP3K8 gene Mediating Memory Messenger RNA Molecular Molecular Biology Mus Natural Killer Cells Pathologic Pathway interactions Phosphotransferases Play Predisposition Process Production Proteins Regulation Research Research Personnel Resistance to infection Rheumatoid Arthritis Role Signal Pathway Signal Transduction Signaling Molecule T-Lymphocyte T-Lymphocyte Subsets Techniques Testing Th1 Cells Therapeutic Intervention Virus Diseases Work bactericide base cell type cytokine cytotoxic defined contribution infectious disease model insight kinase inhibitor macrophage novel programs response treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Cytokines mediate virtually every facet of immunity including lymphoid development, homeostasis, differentiation, tolerance and memory. Interleukin (IL)-12 production during infection determines the type and duration of adaptive immune response through the induction of the pro-inflammatory cytokine, interferon(IFN)-gamma. Defects in signaling via IL-12/IFN-gamma are associated with susceptibility to infections. Of equal concern is that dysregulation of IL-12/IFN-gamma is associated with the development of autoimmunity. Therefore, a comprehensive understanding of the IL-12 signaling pathway is crucial for the development of novel treatment strategies. Currently, our knowledge of IL-12 signaling intermediates is quite incomplete. In an attempt to gain insight into the molecular basis of IL-12's action we identified the serinethreonine kinase, Tpl2, as an IL-12-inducible gene. Because of its function as a kinase, we hypothesize that Tpl2 is a critical intermediate in IL-12 signaling per se that is required for IFN-gamma production, resistance to infection, and, in pathologic settings, the development of autoimmune disease. In order to broaden our understanding of the molecular biology of Tpl2 as it relates to IL-12-mediated IFN-gamma production we propose (1) to define the biochemical pathway that links Tpl2 to IL-12 signaling and (2) to characterize the role of Tpl2 in IFN-gamma production by T and NK cells and its contribution to host defense and the development of autoimmunity. Preliminary data confirm that Tpl2 is regulated by IL-12 in both T and NK cells and is required for the production of IFN-gamma by T cells. We will use standard biochemical techniques including immunoblotting and kinase assay to dissect the signaling role of Tpl2. We will further test our hypotheses by observing the immune responses of Tpl2-deficient mice in murine models of infectious disease and autoimmunity. Due to its causative role in autoimmunity, blockade of IL-12 signaling would be an attractive means for intervention. Because kinases have been implicated in the development of inflammatory diseases, the modulation of kinase activity has become an active area of research in new drug design. If the proposed work demonstrates that Tpl2 is critical in the development of autoimmune disease through the regulation of IL-12-induced production of IFN-gamma, then it will provide a rationale for the development of a Tpl2 selective kinase inhibitor for use in the treatment of human autoimmune diseases.

描述（由申请人提供）：细胞因子几乎介导免疫的各个方面，包括淋巴发育、体内平衡、分化、耐受性和记忆。感染期间白细胞介素 (IL)-12 的产生通过诱导促炎细胞因子干扰素 (IFN)-γ 来决定适应性免疫反应的类型和持续时间。 IL-12/IFN-gamma 信号传导缺陷与感染易感性相关。同样令人担忧的是，IL-12/IFN-γ 的失调与自身免疫的发展有关。因此，全面了解 IL-12 信号通路对于开发新的治疗策略至关重要。目前，我们对 IL-12 信号中间体的了解还很不完整。为了深入了解 IL-12 作用的分子基础，我们将丝氨酸苏氨酸激酶 Tpl2 鉴定为 IL-12 诱导基因。由于其作为激酶的功能，我们假设 Tpl2 是 IL-12 信号转导本身的关键中间体，它是 IFN-γ 产生、抗感染以及在病理情况下发展自身免疫性疾病所必需的。为了扩大我们对 Tpl2 分子生物学的理解，因为它与 IL-12 介导的 IFN-γ 产生相关，我们建议 (1) 定义将 Tpl2 与 IL-12 信号传导联系起来的生化途径，以及 (2) 表征Tpl2 在 T 细胞和 NK 细胞产生 IFN-γ 中的作用及其对宿主防御和自身免疫发展的贡献。初步数据证实，Tpl2 在 T 细胞和 NK 细胞中均受 IL-12 调节，并且是 T 细胞产生 IFN-γ 所必需的。我们将使用标准生化技术（包括免疫印迹和激酶测定）来剖析 Tpl2 的信号传导作用。我们将通过观察感染性疾病和自身免疫小鼠模型中 Tpl2 缺陷小鼠的免疫反应来进一步检验我们的假设。由于其在自身免疫中的致病作用，阻断 IL-12 信号传导将是一种有吸引力的干预手段。由于激酶与炎症性疾病的发展有关，因此激酶活性的调节已成为新药设计研究的活跃领域。如果拟议的工作证明 Tpl2 通过调节 IL-12 诱导的 IFN-γ 产生而在自身免疫性疾病的发展中发挥关键作用，那么它将为开发用于治疗的 Tpl2 选择性激酶抑制剂提供理论依据人类自身免疫性疾病。