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辅助细胞群的特征。 Th17 细胞和 IL-17 在细胞外病原体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 在控制由共生酵母白色念珠菌引起的皮肤粘膜真菌感染中发挥着特别重要的作用。事实上，具有 IL-17 受体缺陷或具有 IL-17 抗体的人类或小鼠非常容易患口腔和皮肤粘膜念珠菌病。然而，IL-17 及其受体用于实现对真菌免疫的具体信号通路尚不清楚。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? 的选择性翻译，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 的生物学作用是什么？尚未证实真菌感染的替代翻译，并且与 IL-17 的具体联系尚不清楚。该提案研究了 IL-17-C/EBP 的两个方面？信号通路。目标 1 将评估 IL-17 调节 C/EBP 选择性翻译的分子机制。我们将确定 (i) C/EBP 中上游开放阅读框 (uORF) 的作用，以及 (ii) PI3K/AKT/mTOR 和 PKR 信号通路在 IL-17 介导的 C/EBP 中的作用？另类翻译。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）的替代翻译，这是一种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 最常见（“LAP”）亚型的敲入小鼠。将使用这种口腔念珠菌病模型来研究 LAP 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？体外和体内下游影响。了解 IL-17 介导信号传导的机制，特别是在感染情况下，可能有助于开发受 IL-17 影响的疾病的药物、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作用对于合理的药物设计非常重要。然而，人们对 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? 替代翻译的影响，这是已知调节 IL-17 介导的信号传导的事件。

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