Regulation of Immunity and Inflammation by TIPE2

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沉淀变化保持在最低限度，以便免疫反应消除有关抗原，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，我们最近发现了肿瘤坏死因子1诱导蛋白8 （TNFAIP8或TIPE）家族的一个新成员，被命名为TIPE2，它优先在淋巴组织和炎症组织中表达。tipe2缺陷小鼠发育正常，但会出现自发性炎症疾病，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缺陷小鼠也对脓毒性休克过敏，tipe2缺陷细胞对toll样受体（TLR）和T细胞受体（TCR）信号反应过度。重要的是，TIPE2与caspase-8结合，抑制活化蛋白(AP)-1和核因子(NF)-:B的活化，同时促进死亡受体诱导的细胞凋亡。因此，TIPE2是一种新的抗炎蛋白，可负调节先天免疫和适应性免疫，其在淋巴组织和炎症组织中的选择性表达可防止高反应性并维持免疫稳态。本研究计划的目标是确定TIPE2负性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的激活，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-？B激酶)和caspase-8。这一理论将在分子、细胞和有机体水平的炎症模型中得到检验。具体目的是：1)确定TIPE2负性调节免疫和炎症的细胞机制；2)确定TIPE2负性调节AP-1和NF-？B信号通路。

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.