Regulation of Immunity and Inflammation by TIPE2

TIPE2 对免疫和炎症的调节

• 批准号: 7802078
• 负责人: Youhai H Chen
• 金额: $ 38.98万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-09 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7802078
• 关键词: Anti-Inflammatory Agents; Anti-inflammatory; Antigen Receptors; Antigens; Apoptosis; B-Cell Lymphomas; Binding; Cell Death; Cell Differentiation process; Cells; Cessation of life; Complement Factor B; Development; Disease; Ensure; Family; Gene Mutation; Genes; Goals; Homeostasis; Immune; Immune Cell Activation; Immune response; Immune system; Immunity; Inflammation; Inflammatory; Interleukin-10; Interleukin-17; Interleukin-6; Interleukins; Knock-out; Lead; Lymphoid; Lymphoid Cell; Mediating; Microarray Analysis; Modeling; Molecular; Mus; Myelogenous; Nuclear; Organ; Organism; Pathway interactions; Phosphotransferases; Production; Property; Proteins; Receptor Activation; Receptor Signaling; Regulation; Research Proposals; Resistance; Role; Septic Shock; Signal Pathway; Splenomegaly; T-Cell Receptor; T-Lymphocyte; Testing; Tissues; Toll-like receptors; Transforming Growth Factors; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; adaptive immunity; base; caspase-8; cytokine; inhibitor/antagonist; macrophage; mammalian genome; member; mucosa-associated lymphoid tissue lymphoma; novel; nuclear factor 1; premature; prevent; public health relevance; receptor; selective expression; theories; transcription factor; treatment strategy

DESCRIPTION (provided by applicant): Immune homeostasis is an inherent property of the immune system. It ensures that any antigen- precipitated change of the immune system is kept to the minimum so that the immune responses eliminate the antigen in question but do not lead to fatal inflammatory diseases. The molecular mechanisms through which immune homeostasis is maintained are not fully understood. Using a high throughput gene microarray technology, we recently identified a novel member of the tumor necrosis factor-1-induced protein 8 (TNFAIP8 or TIPE) family, designated TIPE2, which is preferentially expressed in lymphoid and inflamed tissues. TIPE2-deficent mice develop normally, but suffer from spontaneous inflammatory diseases characterized by multi- organ inflammation, splenomegaly, heightened inflammatory cytokine production and premature death. TIPE2-deficient mice are also hypersensitive to septic shock, and TIPE2-deficient cells are hyper-responsive to Toll-like receptor (TLR) and T cell receptor (TCR) signaling. Importantly, TIPE2 binds to caspase-8, and inhibits activating protein (AP)-1 and nuclear factor (NF)-:B activation while promoting death receptor-induced apoptosis. Thus, TIPE2 is a novel anti-inflammatory protein that negatively regulates both innate and adaptive immunity, and its selective expression in lymphoid and inflamed tissues prevents hyper-responsiveness and maintains immune homeostasis. The goal of this research proposal is to define the cellular and molecular mechanisms through which TIPE2 negatively regulates immunity and inflammation. We hypothesize that TIPE2 inhibits TLR and TCR activation by blocking the functions of the activation receptor-induced signalosome (ARIS) that contains Bcl10 (B cell lymphoma 10), MALT1 (mucosa-associated lymphoid tissue lymphoma translocation gene 1), IKK (Inhibitor of NF-?B kinase) and caspase-8. This theory will be tested in models of inflammation at molecular, cellular and organismal levels. The specific aims are: 1) to define the cellular mechanisms through which TIPE2 negatively regulates immunity and inflammation, and 2) to define the molecular mechanisms through which TIPE2 negatively regulates AP-1 and NF-?B signaling pathways. PUBLIC HEALTH RELEVANCE: The proposed studies in this application will 1) help advance our understanding of a novel pathway of immune regulation, and 2) aid in the development of TIPE2-based strategies for the treatment of inflammatory diseases.

描述（由申请人提供）：免疫稳态是免疫系统的固有特性。它确保免疫系统的任何抗原引发的变化保持在最低限度，以便免疫反应消除有问题的抗原，但不会导致致命的炎症性疾病。维持免疫稳态的分子机制尚不完全清楚。利用高通量基因微阵列技术，我们最近鉴定了肿瘤坏死因子1诱导蛋白8（TNFAIP8或TIPE）家族的一个新成员，命名为TIPE2，它优先在淋巴和炎症组织中表达。 TIPE2缺陷小鼠发育正常，但患有自发性炎症性疾病，其特征是多器官炎症、脾肿大、炎症细胞因子产生增加和过早死亡。 TIPE2 缺陷小鼠也对感染性休克过敏，并且 TIPE2 缺陷细胞对 Toll 样受体 (TLR) 和 T 细胞受体 (TCR) 信号传导过度反应。重要的是，TIPE2 与 caspase-8 结合，抑制激活蛋白 (AP)-1 和核因子 (NF)-:B 激活，同时促进死亡受体诱导的细胞凋亡。因此，TIPE2是一种新型抗炎蛋白，可负调节先天性和适应性免疫，其在淋巴和发炎组织中的选择性表达可防止过度反应并维持免疫稳态。该研究计划的目标是确定 TIPE2 负向调节免疫和炎症的细胞和分子机制。我们假设 TIPE2 通过阻断激活受体诱导的信号体 (ARIS) 的功能来抑制 TLR 和 TCR 激活，该信号体包含 Bcl10（B 细胞淋巴瘤 10）、MALT1（粘膜相关淋巴组织淋巴瘤易位基因 1）、IKK（NF-κB 激酶抑制剂）和 caspase-8。该理论将在分子、细胞和有机体水平的炎症模型中得到检验。具体目标是：1) 明确 TIPE2 负向调节免疫和炎症的细胞机制，2) 确定 TIPE2 负向调节 AP-1 和 NF-κB 信号通路的分子机制。 公共健康相关性：本申请中拟议的研究将 1) 帮助增进我们对免疫调节新途径的理解，2) 帮助开发基于 TIPE2 的炎症性疾病治疗策略。