Mechanism of Modulation of Interleukin-12 Production by Triptolide

雷公藤甲素调节白细胞介素 12 产生的机制

• 批准号: 7495521
• 负责人: XIAOJING MA
• 金额: $ 19.26万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7495521
• 关键词: Address; Antibodies; Antigen-Presenting Cells; Asthma; Atopic Dermatitis; Autoimmune Diseases; Back; Cell Maturation; China; Chinese Herbs; Complement; Dendritic Cells; Development; Disease; Far East; Gene Expression; Generations; Genetic Transcription; Graft Rejection; Growth; Host Defense; IL9 gene; Infection; Inflammatory; Inflammatory Bowel Diseases; Interferons; Interleukin-12; Lupus Erythematosus; Macrophage Activation; Malignant - descriptor; Malignant Neoplasms; Mediating; Medicine; Modality; Molecular; Multiple Sclerosis; Natural Killer Cells; Nephritis; Pathogenesis; Pathway interactions; Plants; Prevention; Production; Promoter Regions; Psoriasis; Relative (related person); Resistance; Response Elements; Rheumatoid Arthritis; Signal Transduction; Systemic Lupus Erythematosus; T-Lymphocyte; Th1 Cells; Therapeutic; Therapeutic Uses; Toxic effect; Transcriptional Activation; Tripterygium wilfordii; cytokine; interleukin-23; pathogen; transcription factor; triptolide

DESCRIPTION (provided by applicant): Interleukin-12 (IL-12) is a heterodimeric cytokine composed of the p40 and p35 chains. It is produced by antigen-presenting cells (APC) and is a key factor in the induction of T cell-dependent and independent activation of macrophages, Natural Killer (NK) cells, generation of T helper type 1 (Th1) cells and cytotoxic T lymphocytes (CTL), induction of opsonizing, complement-fixing antibodies, and resistance to intracellular infections, and malignant growth. IL-12 and its relative IL-23, which shares the p40 chain with IL-12 together with its unique chain of p19, have also been strongly implicated in the pathogenesis of several types of autoimmune disorders such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis, inflammatory bowel disease (IBD), and asthma. Triptolide is a biologically active component purified from Chinese herbal plant Tripterygium wilfordii Hook F. (TWHF). The therapeutic use of TWHF in China as a natural medicine can be traced back several centuries. It is widely used in East Asia for treatment of SLE, RA, nephritis, Bechect's disease, psoriasis, atopic dermatitis, asthma, and very recently in prevention of transplant rejection, with little toxicity. Our own preliminary studies indicate that triptolide is able to strongly inhibit dendritic cell (DC) maturation and function including the synthesis of cytokines such as IL-12 and IL-23. In this project, we will investigate the molecular mechanisms whereby triptolide inhibits the transcription of the p40 gene encoding the shared subunit of IL-12 and IL-23 in APCs. Specifically, we will elucidate the essential transcription factors targeted by triptolide in its inhibition of p40 gene expression, as well as the upstream signaling steps that mediate the inhibition. Understanding these mechanisms at the molecular level will benefit the development of therapeutic modalities using triptolide or its derivatives in the treatment of inflammatory autoimmune disorders.

描述（由申请人提供）：白细胞介素12（IL-12）是一种由p40和p35链组成的异二聚体细胞因子。它由抗原呈递细胞 (APC) 产生，是诱导巨噬细胞、自然杀伤 (NK) 细胞、T 辅助细胞 (Th1) 细胞和细胞毒性 T 细胞的 T 细胞依赖性和独立激活的关键因素。淋巴细胞（CTL）、诱导调理、补体固定抗体、抵抗细胞内感染和恶性生长。 IL-12 及其相关的 IL-23 与 IL-12 共享 p40 链以及其独特的 p19 链，也与多种自身免疫性疾病的发病机制密切相关，例如系统性红斑狼疮 (SLE)、类风湿性关节炎（RA）、多发性硬化症、炎症性肠病（IBD）和哮喘。 雷公藤甲素是从中草药雷公藤雷公藤 (Tripterygium wilfordii Hook F., TWHF) 中纯化得到的生物活性成分。 TWHF 作为天然药物在中国的治疗用途可以追溯到几个世纪前。它在东亚广泛用于治疗系统性红斑狼疮、类风湿性关节炎、肾炎、白克氏病、牛皮癣、特应性皮炎、哮喘，最近还用于预防移植排斥，毒性很小。我们自己的初步研究表明，雷公藤甲素能够强烈抑制树突状细胞 (DC) 的成熟和功能，包括细胞因子（如 IL-12 和 IL-23）的合成。 在本项目中，我们将研究雷公藤内酯醇抑制 APC 中编码 IL-12 和 IL-23 共享亚基的 p40 基因转录的分子机制。具体来说，我们将阐明雷公藤内酯醇在抑制 p40 基因表达时靶向的重要转录因子，以及介导抑制作用的上游信号传导步骤。在分子水平上了解这些机制将有利于开发使用雷公藤甲素或其衍生物治疗炎症性自身免疫性疾病的治疗方式。