Mechanism of Modulation of Interleukin-12 Production by Triptolide

描述（由申请人提供）：白细胞介素-12（IL-12）是一种由p40和p35链组成的异源二聚体细胞因子。它由抗原呈递细胞（APC）产生，并且是诱导巨噬细胞、自然杀伤（NK）细胞的T细胞依赖性和非依赖性活化、T辅助1型（Th 1）细胞和细胞毒性T淋巴细胞（CTL）的产生、诱导调理作用、补体固定抗体以及对细胞内感染和恶性生长的抗性的关键因子。IL-12及其相对的IL-23（其与IL-12共享p40链以及其独特的p19链）也强烈地涉及几种类型的自身免疫性疾病的发病机制，例如系统性红斑狼疮（SLE）、类风湿性关节炎（RA）、多发性硬化、炎性肠病（IBD）和哮喘。 雷公藤内酯醇是从中草药雷公藤中分离得到的一种生物活性成分。（TWHF）。雷公藤在中国作为一种天然药物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SLE、RA、肾炎、Bechect病、银屑病、特应性皮炎、哮喘，最近还用于预防移植排斥反应，毒性很小。我们自己的初步研究表明，雷公藤内酯醇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。 在这个项目中，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其抑制p40基因表达的目标，以及介导抑制的上游信号步骤的基本转录因子。在分子水平上理解这些机制将有利于开发使用雷公藤内酯醇或其衍生物治疗炎症性自身免疫性疾病的治疗模式。

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.