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是一种促炎细胞因子，是新描述的“Th17”CD4+ T辅助人群的标志。Th17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。我们和其他人最近的许多研究表明，IL-17在控制由共生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，IL-17受体缺乏或IL-17抗体的人或小鼠极易患口腔和皮肤粘膜念珠菌病。然而，IL-17及其受体实现对真菌免疫的具体信号通路在很大程度上是未知的。我们已经证明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？这影响了其调节下游基因表达的能力，从而影响了免疫反应。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的靶基因。然而，C/EBP的生物学作用？真菌感染的替代翻译尚未被证实，与IL-17的具体联系尚不清楚。本文研究了IL-17-C/EBP？信号通路。目的1将评估IL-17调控C/EBP替代翻译的分子机制。我们将确定(i)上游开放阅读框架（uORF）在C/EBP中的作用？（ii） PI3K/AKT/mTOR和PKR信号通路在il -17介导的C/EBP中的作用？选择翻译。在目标2中，我们将确定C/EBP的生物学意义。口咽念珠菌病（OPC，鹅口疮）是一种由白色念珠菌引起的强烈依赖il -17的粘膜感染。为此，我们将利用不能产生C/EBP?最常见（“LAP”）亚型的敲入小鼠。LAP缺乏的功能后果将使用这种口腔念珠菌病模型进行研究。总的来说，这些研究将有助于确定IL-17如何调节C/EBP？体外和体内的下游影响。了解IL-17介导信号传导的机制，特别是在感染的情况下，可能有助于开发针对IL-17影响的疾病的药物、疫苗或治疗方法。

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