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多种病原体的免疫反应中起着至关重要的作用。我们培育了一株IL-27受体（WSX-1）基因缺失的小鼠，并证明这些小鼠对利什曼原虫主要感染表现出显著的易感性。通过进一步阐明IL-27R下游的信号转导机制，我们已经表明，在IL-12之前，IL-27/IL-27R （WSX-1）在Th1分化的初始承诺中至关重要。此外，IL-27/WSX-1也被证明具有免疫调节功能，通过抑制一些原生动物感染过程中促炎细胞因子的产生。在目前的研究中，我们进一步分析了IL-27的免疫调节作用，并报道了在缺乏IL-27信号的情况下，由于炎症反应的增强，变应性哮喘加剧，并且在结核分枝杆菌感染期间发生致命性全身炎症。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缺乏伴随着膜性肾小球肾炎（MGN），而不是野生型小鼠的弥漫性增生性肾小球肾炎。据我们所知，这是第一次出现自发发展成MGN的小鼠模型。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诱导，STAT1激活至关重要，对于免疫调节，STAT3激活很重要；进一步阐明IL-27的作用和机制是IL-27治疗应用的必要条件。

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.