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

细胞因子/细胞因子受体网络在建立针对各种病原体的免疫反应中至关重要。我们已经产生了一个系的小鼠IL-27受体（WSX-1）基因缺陷，并已证明，小鼠表现出显着的易感性对利什曼原虫感染受损的IFN-γ的生产。通过进一步阐明IL-27 R下游的信号转导机制，我们已经表明IL-27/IL-27 R（WSX-1）在IL-12之前在Th 1分化的初始定型中是至关重要的。此外，IL-27/WSX-1还显示出通过抑制某些原生动物感染期间的促炎细胞因子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，并报告说，由于在缺乏IL-27信号传导的情况下增强的炎症反应，过敏性哮喘加重，并且在结核分枝杆菌感染期间发生致命的全身炎症。在MRL/lpr小鼠中，其发展为人类系统性狼疮样自身免疫性疾病，IL-27 R的缺乏伴随膜性肾小球肾炎（MGN），而不是野生型小鼠中的弥漫性增殖性肾小球肾炎。据我们所知，这是第一次提出的一系列模型小鼠自发发展MGN。对于IL-27的双重作用，我们还研究了信号转导机制，并发现对于Th 1诱导，STAT 1活化是关键的，对于免疫调节，STAT 3活化是重要的; IL-27的治疗应用需要进一步阐明IL-27的作用和机制。

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.