Immunotoxicity of indirubin, a plant-based AhR ligand

植物性 AhR 配体靛玉红的免疫毒性

• 批准号: 6955384
• 负责人: CHARLES D RICE
• 金额: $ 22.05万
• 依托单位: CLEMSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6955384
• 关键词: antiinflammatory agents; antineoplastics; aromatic hydrocarbon receptor; clinical research; gene expression; growth inhibitors; human tissue; immunotoxicity; kinase inhibitor; laboratory mouse; plant extracts; receptor binding; transcription factor

DESCRIPTION (provided by applicant): Nutraceuticals are a multibillion dollar industry in the USA. For reasons of both marketing strategy and antidotal evidence, oriental herbals are touted as having great promise for ameliorating a variety of diseases. Oriental herbal supplements are perhaps the best example of products readily consumed by the American public without adequate knowledge of efficacy or safety. As a case in point, an active ingredient in Chinese herbals prepared from Polygonum tinctorium has been isolated that inhibits cyclin-dependent kinases and glycogen synthase kinase thereby inhibiting proliferation of leukemia cells. Extracts from this plant enhance detoxication processes and they have potent antiinflammatory properties. The biological activity of the active ingredient has been traced to an indole-metabolite of tryptophan that is further metabolized to two end products, indigo and indirubin. Indirubin is now known to be the active anti-neoplastic and anti-inflammatory ingredient in Polygonum tinctorium extracts. Indirubin binds to the cytosolic aryl hydrocarbon receptor (AhR), a transcription factor, with high affinity and activates the translocation of the ligand-receptor complex to the nucleus, leading to the expression of a suite of genes. Surprisingly indirubin binds to the AhR with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-like affinity. High affinity binding of indirubin to the AhR is an alarming observation because most agents that bind with high affinity to the AhR are immunotoxic. Our preliminary data show that indirubin is a potent inducer of CYP1A1 in differentiated human macrophages. Furthermore indirubin potentiates LPS-stimulated macrophage activation. In addition, indirubin alters the expression of indoleamine 2, 3-dioxygenase (IDO), an enzyme not yet described as being linked to AhR activation. IDO modulation by indirubin is intriguing because several recent studies confirm that tryptophan metabolism and reduction by IDO-alters T-cell responses. Taken together with other preliminary data, including gene array analysis, RT-PGR and protein expression profiles, it appears that indirubin has the potential to act as a TCDD-like compound. To date information regarding potentially adverse effects of novel plant-derived AhR ligands like indirubin on immune function is lacking of particular importance to immune function, cellular and molecular events involved in macrophage differentiation and activation leading to altered proinflammatory events may be affected by plant-based AhR- ligands. The following proposal tests the hypothesis that indirubin is a potent immunotoxic compound.

描述（由申请人提供）：营养学是美国一个数十亿美元的行业。出于营销策略和解毒证据的原因，东方草药被吹捧为可以改善各种疾病的巨大希望。东方草药补充剂也许是美国公众易于消费的产品的最佳例子，而没有足够的功效或安全性知识。一个很好的例子，已经分离出了由多边形tinter虫制备的中等草药中的活性成分，该成分已被抑制细胞周期蛋白依赖性激酶和糖原合酶激酶，从而抑制白血病细胞的增殖。该植物的提取物增强了解毒过程，并具有有效的抗炎特性。活性成分的生物学活性已被追溯到色氨酸的吲哚 - 代谢物，该吲哚 - 代谢物进一步代谢为两种终极产物Indigo和Indirubin。现在已知内丁蛋白是多边形提取物中的活性抗肿瘤和抗炎成分。 Intirubin结合具有高亲和力的转录因子的胞质芳基烃受体（AHR），并激活配体受体复合物与细胞核的转运，从而导致基因套件的表达。令人惊讶的是，单胞纤维蛋白与2,3,7,8-四氯迪本佐-P-二恶英（TCDD）类似亲和力结合AHR。单宗蛋白与AHR的高亲和力结合是一个令人震惊的观察结果，因为大多数与AHR高亲和力结合的药物都是免疫毒性的。我们的初步数据表明，Indirubin是分化人类巨噬细胞中CYP1A1的有效诱导剂。此外，Indirubin增强了LPS刺激的巨噬细胞激活。此外，Indirubin改变了吲哚胺2、3-二加氧酶（IDO）的表达，这是一种尚未被描述为与AHR激活相关的酶。 Indirubin的IDO调制很有趣，因为最近的几项研究证实，色氨酸代谢和Ido-Alters T细胞反应的减少。结合其他初步数据，包括基因阵列分析，RT-PGR和蛋白质表达谱，看来Indirubin具有充当TCDD类化合物的潜力。迄今为止，有关新型植物衍生的AHR配体（例如Indirubin）对免疫功能的潜在不利影响的信息缺乏对免疫功能，巨噬细胞分化涉及的细胞和分子事件的重要性，并激活可能会受到基于植物的AHR-AHR-ligands的影响。以下提案检验了单胞纤维蛋白是一种有效的免疫毒性化合物的假设。

项目成果

3,4-Dihydroxy-benzohydroxamic acid (Didox) suppresses pro-inflammatory profiles and oxidative stress in TLR4-activated RAW264.7 murine macrophages.

• DOI: 10.1016/j.cbi.2015.03.027
• 发表时间: 2015-05-25
• 期刊: CHEMICO-BIOLOGICAL INTERACTIONS
• 影响因子: 5.1
• 作者: Matsebatlela, Thabe M.;Anderson, Amy L.;Gallicchio, Vincent S.;Elford, Howard;Rice, Charles D.
• 通讯作者: Rice, Charles D.

Expression of the Major Vault Protein (MVP) and Cellular Vault Particles in Fish.

• DOI: 10.1002/ar.23645
• 发表时间: 2017-11
• 期刊: Anatomical record (Hoboken, N.J. : 2007)
• 作者: Margiotta AL;Bain LJ;Rice CD
• 通讯作者: Rice CD