PDF(Pubmed)
Abstract：
Cytokines are crucial molecules for maintaining the proper functioning of the immune system. Nevertheless, a dysregulation of cytokine expression could be involved in the pathogenesis of autoimmune diseases. Interleukin (IL)-15 is a key factor for natural killer cells (NK) and CD8 T cells homeostasis, necessary to fight cancer and infections but could also be considered as a pro-inflammatory cytokine involved in autoimmune inflammatory disease, including rheumatoid arthritis, psoriasis, along with tumor necrosis factor alpha (TNF-α), IL-6, and IL-1β. The molecular mechanisms by which IL-15 exerts its inflammatory function in these diseases are still unclear. In this study, we generated an IL-15-derived molecule called NANTIL-15 (New ANTagonist of IL-15), designed to selectively inhibit the action of IL-15 through the high-affinity trimeric IL-15Rα/IL-2Rβ/γc receptor while leaving IL-15 signaling through the dimeric IL-2Rβ/γc receptor unaffected. Administrating of NANTIL-15 in healthy mice did not affect the IL-15-dependent cell populations such as NK and CD8 T cells. In contrast, we found that NANTIL-15 efficiently reduced signs of inflammation in a collagen-induced arthritis model. These observations demonstrate that the inflammatory properties of IL-15 are linked to its action through the trimeric IL-15Rα/IL-2Rβ/γc receptor, highlighting the interest of selectively targeting this receptor.
摘要：
细胞因子是维持免疫系统正常功能的关键分子。然而，细胞因子表达失调可能与自身免疫性疾病的发病机制有关。白细胞介素（IL）-15是自然杀伤细胞（NK）和CD8T细胞稳态的关键因素，必须对抗癌症和感染，但也可以被认为是参与自身免疫性炎性疾病的促炎细胞因子，包括类风湿性关节炎,牛皮癣,随着肿瘤坏死因子α（TNF-α），IL-6和IL-1β。IL-15在这些疾病中发挥其炎症功能的分子机制尚不清楚。在这项研究中,我们产生了一种IL-15衍生的分子，称为NANTIL-15（IL-15的新拮抗剂），旨在通过高亲和力三聚体IL-15Rα/IL-2Rβ/γc受体选择性抑制IL-15的作用，而通过二聚体IL-2Rβ/γc受体的IL-15信号传导不受影响。在健康小鼠中施用NANTIL-15不影响IL-15依赖性细胞群体,例如NK和CD8T细胞。相比之下,我们发现,在胶原诱导的关节炎模型中,NANTIL-15可有效降低炎症的体征.这些观察结果表明，IL-15的炎症特性与其通过三聚体IL-15Rα/IL-2Rβ/γc受体的作用有关，突出了选择性靶向该受体的兴趣。
