IL-17-Induced Regulation of C/EBPbeta

描述（由申请人提供）：IL-17是一种促炎细胞因子，是新描述的“Th 17”CD 4 + T辅助细胞群的特征。Th 17细胞和IL-17在对细胞外病原体的免疫中发挥重要的宿主防御作用。我们小组和其他人最近的许多研究表明，IL-17在控制由真菌酵母菌白色念珠菌引起的皮肤粘膜真菌感染中起着特别重要的作用。事实上，具有IL-17受体缺陷或具有针对IL-17的抗体的人或小鼠高度倾向于口腔和粘膜皮肤念珠菌病。然而，IL-17及其受体用于实现对真菌的免疫的特定信号传导途径在很大程度上是未知的。我们已经表明，IL-17激活CCAAT增强子结合蛋白B（C/EBP？）IL-17是一种转录因子，它是激活大多数IL-17靶基因所必需的。特别是，IL-17控制C/EBP？的替代翻译，这会影响其调节下游基因表达的能力，从而影响免疫反应。在细菌感染中，C/EBP的替代翻译？是有效免疫所必需的，许多受影响的基因是IL-17靶基因。然而，C/EBP的生物学作用？真菌感染的替代翻译尚未得到证实，与IL-17的特异性联系尚不清楚。本提案调查两个方面的IL-17-C/EBP？信号通路目的1将评估IL-17调节C/EBP？替代翻译的分子机制。我们将确定（i）C/EBP？中上游开放阅读框（uORF）的作用，PI 3 K/AKT/mTOR和PKR信号通路在IL-17介导的C/EBP中的作用？替代翻译在目的2，我们将确定的生物学意义的C/EBP？口咽念珠菌病（OPC，鹅口疮），一种由白色念珠菌引起的强烈IL-17依赖性粘膜感染的替代翻译。为此，我们将利用不能产生C/EBP？的最常见（“β”）同种型的敲入小鼠。将使用该口腔念珠菌病模型研究β-内酰胺酶缺乏的功能后果。总的来说，这些研究将有助于确定IL-17如何调节C/EBP？在体外和下游的影响在体内。了解IL-17介导信号传导的机制，特别是在感染的背景下，可能有助于开发受IL-17影响的药物，疫苗或治疗方法。 公共卫生相关性：了解IL-17在感染免疫调节中的作用及其在自身免疫中的潜在病理作用对于合理设计药物具有重要意义。然而，IL-17调节这些过程的基本机制知之甚少。本研究将研究IL-17介导转录因子C/EBP？选择性翻译的作用，已知该事件调节IL- 17介导的信号传导。

DESCRIPTION (provided by applicant): IL-17 is a pro-inflammatory cytokine that is the signature of the newly described "Th17" CD4+ T helper population. Th17 cells and IL-17 play essential host-defensive roles in immunity to extracellular pathogens. Many recent studies by our group and others demonstrated that IL-17 plays a particularly important role in controlling mucocutaneous fungal infections caused by the commensal yeast, Candida albicans. Indeed, humans or mice with IL-17 receptor deficiencies or with antibodies against IL-17 are highly prone to oral and mucocutaneous candidiasis. However, the specific signaling pathways used by IL-17 and its receptor to accomplish immunity to fungi are largely unknown. We have shown that IL-17 activates the CCAAT enhancer binding protein b (C/EBP?) transcription factor, which is required for activation of a majority of IL-17 target genes. In particular, IL-17 controls the alternative translation of C/EBP?, which impacts its ability to regulate downstream gene expression and therefore shape immune responses. In bacterial infections, alternative translation of C/EBP? is required for effective immunity and many of the genes that are affected are IL-17 target genes. However, the biological role of C/EBP? alternative translation has not been demonstrated for fungal infections and the specific connection to IL-17 is unknown. This proposal investigates two aspects of the IL-17-C/EBP? signaling pathway. Aim 1 will assess molecular mechanisms by which IL-17 regulates alternative translation of C/EBP?. We will determine (i) the role of an upstream open reading frame (uORF) within C/EBP?, and (ii) the role of the PI3K/AKT/mTOR and PKR signaling pathways in IL-17-mediated C/EBP? alternative translation. In Aim 2, we will determine the biological significance of C/EBP? alternative translation in oropharyngeal candidiasis (OPC, thrush), a strongly IL-17-dependent mucosal infection caused by Candida albicans. To this end, we will take advantage of a knockin mouse that cannot generate the most common ("LAP") isoform of C/EBP?. The functional consequences of LAP deficiency will be investigated using this model of oral candidiasis. Collectively, these studies will help determine how IL-17 regulates C/EBP? in vitro and the downstream impact in vivo. Understanding the mechanism by which IL-17 mediates signaling, particularly in the context of infection, may aid in the development of drugs, vaccines or treatments in diseases affected by IL-17. PUBLIC HEALTH RELEVANCE: Understanding the role of IL-17 in regulating immunity to infection and its potential pathological contribution in autoimmunity is important for rational dru design. However, the fundamental mechanism by which IL-17 regulates these processes is poorly understood. This proposed research will study the effects of IL-17 on mediating the alternative translation of the transcription factor C/EBP?, an event that is known to modulate IL- 17-mediated signaling.