Treatment of endotoxin-induced tissue damages by the negative regulation of TLR-mediated signal pathways

通过负调节 TLR 介导的信号通路治疗内毒素引起的组织损伤

• 批准号: 15390220
• 负责人: TSUTSUI Hiroko
• 金额: $ 9.28万
• 依托单位: HYOGO COLLEGE OF MEDICINE
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15390220/
• 关键词: Toll-like receotors; Myeloiddifferentiation factor 88; liver injuries; liver regeneration; SOCS-1; SOCS-3; LPS; Reactivearthritis; SOCS; NK細胞; IFN-γ; ケモカイン; 臓器ホメオスターシス; エンドトキシン・LPS; Propionibacterium acnes

Immunity is largely categorized into two types, adoptive immunity and innate immunity. As compared with innate immunity, acquired immunity has the diversity and the accuracy in its recognition of corresponding antigens based on the DNA rearrangement machineries and hypermutation properties that T cells and B cells selectively possess. Therefore, acquired immunity had been believed to he extremely sophisticated and ideal system for host defense. Innate immunity had been regarded to play a role only as the front line that would drop out after activation of the corresponding acquired immunity. In fact, innate immune constituents, such as dendritic cells(DCs) and macrophages, can promptly respond to microbes and their products without help from additional acquired immune responses, whereas acquired immunity takes long time to be able to exert its full immunological actions. However, recent intensive studies on signaling receptors in the innate immune system, in particular on toll-like rece … More ptors(TLRs), led us to notify its importance comparable to adaptive immunity. After microbial infection, antigen-presenting cells(APCs) composing innate immunity capture the microbial antigens. Simultaneously, the microbial products stimulate the APCs through their TLRs to undergo the appropriate maturation, which is represented by expression of chemokine receptors critical for translocation into the regional lymph nodes and of various co-stimulatory molecules essential for the appropriate activation of T helper cells. These APCs produce a variety of cytokines in response to the TLR ligands of the microbes as well. Unless they experience these biological events through their TLRs, these APCs cannot drive the activation or differentiation of antigen-specific T cells. In particular, certain cytokines, such as IL-12 and IL-18, produced by the APCs are required for the differentiation of naive helper T cells toward the effector cells to eradicate the microbes. Thus, the absence of innate immune responses render mammalian host highly susceptible to pathological organisms.Innate immunity is equipped with various signaling receptors including a TLR family (Janeway and Medzhitov,2002). TLR family consists of more than 10 members. Each member precisely recognizes corresponding molecular patterns associated with pathogens, and exerts its host defensive actions based on their ignorance of host-derived intact components. Indeed, the TLR-mediated signal pathways are essential for microbe expulsion at the early infectious phase. Unexpectedly and importantly, the signalings through TLRs are definitely required for the following activation of the acquired immunity. Lack of the TLR-mediated pathway sometimes causes immature T cell responses and failure in the development of memory T cells, presumably due to the absence of cytokine production and DC maturation and activation, which is normally induced by the activation of the TLR pathway and is required for those immunological events.Like in the case of autoimmunity associated with the dysregulated adaptive immunity, excessive activation of innate immunity causes diseases. It is well documented that the activation of innate immunity by pathogens occasionally causes fatal pathological alterations via aberrant induction of cytokines. Both innate and acquired immune systems complete their proper actions via cognate cellular interactions and cytokine catch bowl. Therefore, it is quite important for homeostatic immune responses to regulate the innate immune responses and adaptive immunity by controlling TLR and cytokine signalings.In this study, we demonstrated that TLR-mediated signaling are essential for the tissue homeostasis in mice. Upon partial hepatectomy, wild-type mice show prompt liver regeneration. However, mutant mice that lack intracellular adaptor molecule essential for the activation of TLR-mediated pathways are defect in the liver regeneration after partial hepatectomy. This clearly indicates that TLR-mediated innate immunity is essential for not only host defense but also tissue homeostasis. Furthermore, we observed that IL-6 but not TNF, both of which are induced by the activation of TLR-mediated signalings, contributes to the development of acute reactive arthritis in mice. Thus, these results indicate that the TLR-mediated pathways play an important role in various biological situations, such as host defense, tissue homeostasis and incidental tissue injuries. Less

免疫主要分为两类：过继性免疫和先天免疫。与先天免疫相比，获得性免疫基于T细胞和B细胞选择性具有的DNA重排机制和超突变特性，对相应抗原的识别具有多样性和准确性。因此，获得性免疫被认为是一种极为完善和理想的宿主防御系统。先天免疫一直被认为只发挥一线作用，在相应的获得性免疫激活后退出。事实上，先天免疫成分，如树突状细胞（dc）和巨噬细胞，可以在没有额外获得性免疫应答的情况下迅速对微生物及其产物作出反应，而获得性免疫需要很长时间才能充分发挥其免疫作用。然而，最近对先天免疫系统中信号受体的深入研究，特别是toll样受体（TLRs），使我们意识到其重要性可与适应性免疫相媲美。微生物感染后，构成先天免疫的抗原呈递细胞（APCs）捕获微生物抗原。同时，微生物产物通过其tlr刺激apc进行适当的成熟，其表现为表达对转运到区域淋巴结至关重要的趋化因子受体和对T辅助细胞的适当激活至关重要的各种共刺激分子。这些apc也会产生多种细胞因子以响应微生物的TLR配体。除非它们通过tlr经历这些生物事件，否则这些apc不能驱动抗原特异性T细胞的激活或分化。特别是，由apc产生的某些细胞因子，如IL-12和IL-18，是幼稚的辅助T细胞向效应细胞分化以消灭微生物所必需的。因此，先天免疫反应的缺乏使哺乳动物宿主极易受到病理生物的影响。先天免疫具有多种信号受体，包括TLR家族（Janeway和Medzhitov，2002）。TLR家族由10多个成员组成。每个成员精确地识别与病原体相关的相应分子模式，并基于它们对宿主衍生的完整成分的无知而发挥宿主防御作用。事实上，tlr介导的信号通路对于早期感染阶段的微生物驱逐至关重要。出乎意料的是，重要的是，通过tlr的信号对于随后获得性免疫的激活是绝对必要的。缺乏TLR介导的通路有时会导致未成熟的T细胞反应和记忆T细胞发育失败，可能是由于缺乏细胞因子的产生和DC成熟和激活，这通常是由TLR通路的激活诱导的，并且是这些免疫事件所必需的。与适应性免疫失调相关的自身免疫一样，先天免疫的过度激活会导致疾病。有充分的证据表明，由病原体激活的先天免疫偶尔会通过异常诱导细胞因子引起致命的病理改变。先天免疫系统和获得性免疫系统都通过同源细胞相互作用和细胞因子捕获碗来完成其适当的动作。因此，通过TLR和细胞因子信号的调控来调节先天免疫和适应性免疫对机体的稳态免疫应答具有重要意义。在这项研究中，我们证明了tlr介导的信号对小鼠组织稳态至关重要。部分肝切除后，野生型小鼠肝脏再生迅速。然而，缺乏激活tlr介导途径所必需的细胞内接头分子的突变小鼠在部分肝切除术后的肝脏再生中存在缺陷。这清楚地表明，tlr介导的先天免疫不仅对宿主防御至关重要，而且对组织稳态也至关重要。此外，我们观察到IL-6而不是TNF（两者都是由tlr介导的信号激活诱导的）有助于小鼠急性反应性关节炎的发展。因此，这些结果表明，tlr介导的途径在多种生物学情况下发挥重要作用，如宿主防御、组织稳态和偶然的组织损伤。少

项目成果

TNF signaling as pleiotropic gates in the liver.

TNF 信号传导作为肝脏中的多效性门控。

• 发表时间: 2004
• 期刊: Hepatol.Res. 31
• 作者: Tsutsui;H. Editorial
• 通讯作者: H. Editorial

Tsutsui, H., 他: "Cytokine-induced inflammatory liver injuries"Curr.Mol.Med.. 7. 545-559 (2003)

Tsutsui，H.，等人：“细胞因子诱导的炎症性肝损伤”Curr.Mol.Med.. 7. 545-559 (2003)

Involvement of Interleukin-18 in Acute Graft-Versus-Host Disease in Mice

• DOI: 10.1097/01.tp.0000137934.25190.b9
• 发表时间: 2004-11
• 期刊: Transplantation
• 影响因子: 6.2
• 作者: H. Itoi;Y. Fujimori;H. Tsutsui;K. Matsui;A. Sugihara;N. Terada;T. Hada;E. Kakishita;H. Okamura;H. Hara;K. Nakanishi

Inhibition by interleukin-18 of the growth of Dunn osteosarcoma cells.

• DOI: 10.1089/107999004322917007
• 发表时间: 2004-07
• 期刊: Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research
• 作者: T. Okamoto;N. Yamada;T. Tsujimura;A. Sugihara;Y. Nishizawa;H. Ueda;S. Kashiwamura;H. Tsutsui;H. Futani;S. Maruo;H. Okamura;N. Terada

サイトカイン・ケモカインのすべて-基礎から最新情報まで-、第3版改訂新版(笠原新平, 松島網冶)

关于细胞因子和趋化因子的一切 - 从基础知识到最新信息 - 第 3 修订版（Shinpei Kasahara，Amiharu Matsushima）

• 发表时间: 2004
• 作者: 筒井ひろ子;中西憲司
• 通讯作者: 中西憲司