IL-17-Induced Regulation of C/EBPbeta

IL-17 诱导的 C/EBPbeta 调节

• 批准号: 8393938
• 负责人: Michelle Rosan Simpson-Abelson
• 金额: $ 5.22万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-12-01 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8393938
• 关键词: Affect; Antibodies; Autoimmunity; B-Lymphocytes; Bacterial Infections; Biological; CCAAT-Enhancer-Binding Protein-beta; CCAAT-Enhancer-Binding Proteins; Candida albicans; Cell Line; Cells; Disease; Event; Fibroblasts; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Grant; Host Defense; Human; Immune response; Immunity; In Vitro; Infection; Inflammation; Inflammatory; Initiator Codon; Interleukin-17; Interleukin-6; Lead; Listeria monocytogenes; Liver; Measures; Mediating; Modeling; Molecular; Mouse Protein; Mucocutaneous Candidiasis; Mus; Mutation; Mycoses; Open Reading Frames; Oral candidiasis; PI3K/AKT; Pathway interactions; Physiologic pulse; Play; Population; Predisposition; Process; Protein Deficiency; Protein Isoforms; Proteins; RNA Interference; Regulation; Research; Reverse Transcriptase Polymerase Chain Reaction; Role; Shapes; Signal Pathway; Signal Transduction; Site; Translations; Vaccines; Yeasts; base; cell type; cytokine; design; drug development; extracellular; fungus; gene induction; human FRAP1 protein; in vivo; inhibitor/antagonist; liver function; macrophage; oropharyngeal thrush; pathogen; receptor; transcription factor

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.

描述（由申请人提供）：IL-17是一种促炎性细胞因子，是新描述的“ TH17” CD4+ T助手群体的特征。 Th17细胞和IL-17在对细胞外病原体的免疫中起着必不可少的宿主防御作用。我们小组和其他人最近的许多研究表明，IL-17在控制由共生酵母白色念珠菌引起的粘膜皮肤真菌感染中起着特别重要的作用。实际上，患有IL-17受体缺乏症或针对IL-17抗体的人或小鼠高度容易出现口服和粘膜念珠菌病。但是，IL-17及其受体用于实现真菌免疫的特定信号通路是未知的。我们已经表明，IL-17激活CCAAT增强子结合蛋白B（C/EBP？）转录因子，这是激活大多数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并因此塑造免疫反应的能力。在细菌感染中，C/EBP的替代翻译？需要有效免疫，许多受影响的基因都是IL-17靶基因。但是，C/EBP的生物学作用？真菌感染尚未证明替代翻译，并且与IL-17的具体连接尚不清楚。该提案研究了IL-17-C/EBP的两个方面？信号通路。 AIM 1将评估IL-17通过调节C/EBP的替代翻译的分子机制。我们将确定（i）上游开放阅读框（UORF）在C/EBP？和（ii）PI3K/AKT/MTOR和PKR信号通路在IL-17介导的C/EBP中的作用吗？替代翻译。在AIM 2中，我们将确定C/EBP的生物学意义？口咽念珠菌病（OPC，Thrush）中的替代翻译，这是由白色念珠菌引起的强烈IL-17依赖性粘膜感染。为此，我们将利用无法生成C/EBP？的最常见（“ Lap”）同工型的敲击鼠。将使用这种口服念珠菌病模型来研究圈缺乏症的功能后果。总的来说，这些研究将有助于确定IL-17如何调节C/EBP？体外和下游影响体内。了解IL-17介导信号传导的机制，尤其是在感染的背景下，可能有助于开发受IL-17影响的疾病中的药物，疫苗或治疗方法。 公共卫生相关性：了解IL-17在调节感染免疫中的作用及其在自身免疫中的潜在病理贡献对于理性DRU设计很重要。但是，IL-17调节这些过程的基本机制知之甚少。这项拟议的研究将研究IL-17对介导转录因子C/EBP的替代翻译的影响，该事件已知会调节IL-17介导的信号传导。

项目成果

CCAAT/Enhancer-binding protein β promotes pathogenesis of EAE.

• DOI: 10.1016/j.cyto.2017.01.005
• 发表时间: 2017-04
• 期刊: Cytokine
• 影响因子: 3.8
• 作者: Simpson-Abelson MR;Hernandez-Mir G;Childs EE;Cruz JA;Poholek AC;Chattopadhyay A;Gaffen SL;McGeachy MJ
• 通讯作者: McGeachy MJ