Analyses of the immunoregulatory mechanisms by IL-12-related cytokines and their receptors

IL-12相关细胞因子及其受体的免疫调节机制分析

• 批准号: 16390145
• 负责人: YOSHIDA Hiroki
• 金额: $ 8.64万
• 依托单位: Saga University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390145/
• 关键词: IL-27; CD4+T cells; inflammation; Infection; autoimmunity; cytokines; Th1; lymphocyte differentiation; WSX-1; 感染症; 自己免疫疾患

Cytokine/cytokine receptor network is critical in the establishment of immune reaction against various pathogens. We have generated a line of mice deficient for IL-27 receptor (WSX-1) gene and have proved that the mice show remarkable susceptibility against Leishmania major infection by impaired IFN-gamma production. By additional elucidation of the signal transduction mechanisms downstream of IL-27R, we have shown that IL-27/IL-27R (WSX-1) is critical in the initial commitment of Th1 differentiation, prior to IL-12. In addition, IL-27/WSX-1 is also shown to have immunoregulatory function by suppression of pro-inflammatory cytokine production during some protozoan infection. In the current study, we further analyzed the immunoregulatory roles of IL-27 and reported that, due to the augmented inflammatory responses in the absence of IL-27 signaling, allergic asthma exacerbated and also that lethal systemic inflammation occurred during Mycobacterium tuberculosis infection. In MRL/lpr mice, which develop human systemic lupus erythematosus-like autoimmune disease, lack of IL-27R was accompanied with membranous glomerulonephritis (MGN), instead of diffuse proliferative glomerulonephritis in the wild-type mice. To the best of our knowledge, this is the first presentation of a line of model mice that spontaneously develop MGN. For the dual roles of IL-27, we also examined the signal transduction mechanisms and have found that, for Th1 induction, STAT1 activation is critical and that, for immunoregulation, STAT3 activation is important ; further elucidation of the roles and mechanisms of IL-27 is required for therapeutic application of IL-27.

细胞因子/细胞因子受体网络在建立对各种病原体的免疫反应中起着至关重要的作用。我们已经建立了一株IL-27受体(WSX-1)基因缺陷的小鼠，并证明了这些小鼠通过抑制干扰素-γ的产生而对重大利什曼原虫感染表现出显著的敏感性。通过进一步阐明IL-27R下游的信号转导机制，我们已经证明IL-27/IL-27R(WSX-1)在Th1分化的初始过程中起着关键作用，先于IL-12。此外，IL-27/WSX-1还被证明在一些原虫感染过程中通过抑制促炎细胞因子的产生而具有免疫调节功能。在目前的研究中，我们进一步分析了IL-27的免疫调节作用，并报道了由于在没有IL-27信号的情况下炎症反应增强，过敏性哮喘加剧，而且在结核分枝杆菌感染期间发生了致命性全身炎症。在发生人类系统性红斑狼疮样自身免疫性疾病的MRL/LPR小鼠中，IL-27R缺乏在野生型小鼠中伴发膜性肾小球肾炎(MGN)，而不是弥漫性增生性肾小球肾炎。据我们所知，这是第一次展示一系列自发发展成MGN的模型鼠。对于IL-27的双重作用，我们还研究了信号转导机制，发现对于Th1的诱导，STAT1的激活是关键的，而对于免疫调节，STAT3的激活是重要的；IL-27的治疗应用需要进一步阐明IL-27的作用和机制。

项目成果

Membranous glomerulonephritis development with Th2-type immune deviations in MRL/lpr mice deficient for IL-27 receptor (WSX-1)

• DOI: 10.4049/jimmunol.175.11.7185
• 发表时间: 2005-12-01
• 期刊: JOURNAL OF IMMUNOLOGY
• 影响因子: 4.4
• 作者: Shimizu, S;Sugiyama, N;Yoshida, H
• 通讯作者: Yoshida, H

Autoamplification of NFATcl expression determines its essential role in bone homeostasis.

NFATcl 表达的自动扩增决定了其在骨稳态中的重要作用。

• 发表时间: 2005
• 期刊: J. Exp. Med. 202
• 作者: Asagiri;M. et al.
• 通讯作者: M. et al.

The Double Identity of WSX-1 (II-27R) as an Initiator and Attenuator of Immune Responses.

WSX-1 (II-27R) 作为免疫反应引发剂和衰减剂的双重身份。

• 发表时间: 2005
• 期刊: Current Immunology Reviews 1
• 作者: Yoshida;H.;Hamano;S.;Miyazaki;Y.
• 通讯作者: Y.

Recent Res Devel Immunology : Research Signpost

免疫学最新研究进展：研究路标

• 发表时间: 2004
• 作者: Yoshida;H.;Hamano;S.;Miyazaki;Y.
• 通讯作者: Y.

Exacerbation of experimental allergic asthma by augmented Th2 responses in WSX-1-deficient mice

• DOI: 10.4049/jimmunol.175.4.2401
• 发表时间: 2005-08-15
• 期刊: JOURNAL OF IMMUNOLOGY
• 影响因子: 4.4
• 作者: Miyazaki, Y;Inoue, H;Yoshida, H
• 通讯作者: Yoshida, H