Biological functions of Interleukin - 26

项目概要/摘要： 在这个建议中，我们将定义一个研究不足的细胞因子白细胞介素-26（IL-26）在粘膜中的功能， 使用人类和斑马鱼模型的屏障。细胞因子对于适应性和非适应性都具有多效性功能。 免疫系统的先天武器，以促进抗菌免疫，调节炎症，并维持 组织内稳态由Th17细胞产生的IL-26与人类的炎性疾病有关，例如 如类风湿性关节炎溃疡性结肠炎和牛皮癣。IL-26在这些炎症中的潜在作用 疾病还不太清楚。由于小鼠不编码IL 26基因，因此针对IL 26基因的生物学的研究 IL-26缺乏。我们对IL-26生物学的理解主要局限于IL-26对 上皮细胞，由于IL-26受体的明显组织和细胞限制。此外，由于IL-26是 在小鼠和其他啮齿类动物中不存在，这对理解其生物学功能构成了重大障碍。作为 因此，IL-26生物学的研究仅限于体外细胞培养模型。然而，我们已经确定了一个 以高度保守的IL-10家族特征基序为特征的人IL-26在斑马鱼中的同源物 和人类的同线性相似它们之间存在着广泛的序列和功能保守性， 人类和斑马鱼的基因组，包括参与先天免疫和适应性免疫的基因。为此我们将 (i)定义人角质形成细胞中IL-26诱导的转录和信号传导网络，和（ii）定义 IL-26在斑马鱼粘膜表面抗菌反应中的作用。拟议的实验将 为IL-26在炎症和抗微生物免疫中的生物学功能提供了前所未有的见解， 这对IL-26在炎症性疾病的发生和发展中的作用具有重要意义。

Project Summary/Abstract: In this proposal, we will define the functions of an understudied cytokine interleukin-26 (IL-26) at the mucosal barrier using human and zebrafish models. Cytokines have pleiotropic functions for both the adaptive and innate arms of the immune system to promote antimicrobial immunity, regulate inflammation, and maintain tissue homeostasis. IL-26, produced by Th17 cells, is associated with inflammatory diseases in humans, such as rheumatoid arthritis, ulcerative colitis, and psoriasis. The underlying role of IL-26 in these inflammatory diseases is not well understood. Since mice do not encode the IL26 gene, studies that address the biology of IL-26 have been lacking. Our understanding of IL-26 biology is primarily restricted to the effect IL-26 has on epithelial cells, due to apparent tissue and cellular restriction of the IL-26 receptor. Moreover, as IL-26 is absent in mice and other rodents, it has posed a significant barrier in understanding its biological functions. As such, studies of IL-26 biology have been limited to in vitro cell culture models. However, we have identified a homolog of human IL-26 in zebrafish that is characterized by a highly conserved IL-10 family signature motif and has similar synteny as in humans. There is extensive sequence and functional conservation between human and zebrafish genomes, including genes involved in innate and adaptive immunity. To this end, we will (i) define the transcription and signaling networks induced by IL-26 in human keratinocytes and (ii) define the role of IL-26 in antimicrobial responses at mucosal surfaces in zebrafish. The proposed experiments will provide unprecedented insight into the biological function of IL-26 in inflammation and antimicrobial immunity, with important implications for the role of IL-26 in initiation and progression of inflammatory disease.