Regulation of Immunity and Inflammation by TIPE2

说明(申请人提供)：免疫动态平衡是免疫系统的固有属性。它确保将任何由抗原引起的免疫系统变化保持在最低限度，以便免疫反应消除相关抗原，但不会导致致命的炎症性疾病。维持免疫动态平衡的分子机制尚不完全清楚。利用高通量基因芯片技术，我们最近发现了肿瘤坏死因子-1诱导蛋白8(TNFAIP8或TIPE)家族中的一个新成员，命名为TIPE2，它优先在淋巴组织和炎症组织中表达。TIPE2基因缺陷小鼠发育正常，但患有以多器官炎症、脾肿大、炎性细胞因子分泌增加和过早死亡为特征的自发性炎症性疾病。TIPE2基因缺陷的小鼠也对感染性休克敏感，TIPE2基因缺陷的细胞对Toll样受体(TLR)和T细胞受体(TCR)信号具有高反应性。重要的是，TIPE2与caspase-8结合，在促进死亡受体诱导的细胞凋亡的同时，抑制激活蛋白(AP)-1和核因子(NF)-B的激活。因此，TIPE2是一种新的抗炎蛋白，它对先天免疫和获得性免疫都有负面调节作用，它在淋巴组织和炎症组织中的选择性表达可以防止高反应性，维持免疫平衡。这项研究计划的目标是确定TIPE2负面调节免疫和炎症的细胞和分子机制。我们推测，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的激活，ARIS含有Bcl10(B细胞淋巴瘤10)、MALT1(黏膜相关淋巴组织淋巴瘤转位基因1)、IKK(核因子-B激酶抑制物)和caspase-8。这一理论将在分子、细胞和机体水平的炎症模型中进行测试。其具体目的是：1)明确TIPE2负性调节免疫和炎症的细胞机制；2)明确TIPE2负性调节AP-1和NF-βB信号通路的分子机制。 公共卫生相关性：本申请中拟议的研究将1)帮助我们加深对免疫调节新途径的理解，2)有助于开发基于TIPE2的治疗炎症性疾病的策略。

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.