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的变化保持在最低限度，使得免疫应答消除所讨论的抗原，但不导致致命的炎性疾病。维持免疫稳态的分子机制尚未完全了解。使用高通量基因微阵列技术，我们最近确定了一个新的成员的肿瘤坏死因子-1诱导蛋白8（TNFAIP 8或TIPE）家族，指定TIPE 2，这是优先在淋巴和炎症组织中表达。TIPE 2缺陷小鼠发育正常，但患有以多器官炎症、脾肿大、炎性细胞因子产生增加和过早死亡为特征的自发性炎性疾病。TIPE 2缺陷型小鼠也对败血性休克过敏，并且TIPE 2缺陷型细胞对Toll样受体（TLR）和T细胞受体（TCR）信号传导过敏。重要的是，TIPE 2结合半胱天冬酶-8，并抑制活化蛋白（AP）-1和核因子（NF）-：B活化，同时促进死亡受体诱导的细胞凋亡。因此，TIPE 2是一种新的抗炎蛋白，其负调节先天免疫和适应性免疫，并且其在淋巴组织和发炎组织中的选择性表达防止高反应性并维持免疫稳态。这项研究的目的是确定TIPE 2负调节免疫和炎症的细胞和分子机制。我们推测TIPE 2通过阻断活化受体诱导的信号体（阿里斯）的功能来抑制TLR和TCR的活化，该信号体包含Bcl 10（B细胞淋巴瘤10）、MALT 1（粘膜相关淋巴组织淋巴瘤易位基因1）、IKK（NF-？B激酶）和半胱天冬酶-8。这一理论将在分子、细胞和有机体水平的炎症模型中进行测试。具体目标是：1）确定TIPE 2负调节免疫和炎症的细胞机制，2）确定TIPE 2负调节AP-1和NF-？B信号通路。 公共卫生相关性：本申请中提出的研究将1）有助于促进我们对免疫调节新途径的理解，2）有助于开发基于TIPE 2的炎症性疾病治疗策略。

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.