PARP-1 in Juvenile Idiopathic Arthritis-associated IL-10 Promoter Polymorphisms

描述（由申请人提供）： 摘要：幼年特发性关节炎（JIA）是儿童期最常见的慢性自身免疫性炎症性疾病。IL-10启动子基因型为-1082A/-819T/-592A（ATA）的患者产生的IL-10较低，可导致过度的炎症反应和更严重的关节炎，表明IL-10基因变异与JIA直接相关。最近，我们确定聚（ADP-核糖）聚合酶1（PARP-1）作为一种新的IL-10基因表达的转录抑制因子与ATA IL-10启动子基因型的结合亲和力增强。因此，我们假设PARP-1介导的IL-10产生抑制对JIA的发病机制很重要，消除这种抑制可能会导致治疗JIA患者的有效疗法。IL-10是多种免疫细胞产生的多效性细胞因子，包括T细胞、B细胞、巨噬细胞和树突细胞。它抑制促炎细胞因子的产生并抑制促炎细胞因子如肿瘤坏死因子-α（TNF-α）的作用。PARP-1是一种高度保守的核锌指蛋白，参与DNA修复、染色质去凝聚和基因表达.我们最近的工作表明，PARP-1与IL-10启动子的结合通过-592A序列多态性增强，并且PARP-1的过表达导致人巨噬细胞中IL-10的产生降低。然而，PARP-1如何调节IL-10的机制细节尚不清楚，必须阐明以开发基于靶向PARP-1的新疗法。因此，本课题的主要目的是：（1）在分子水平上阐明PARP-1调控IL-10基因表达的机制。(2)开发能够逆转表达ATA IL-10启动子基因型的JIA患者中PARP-1介导的IL-10产生抑制的方法。这项研究将使我们能够确定的监管途径，可能会被探索为JIA的治疗干预的潜在目标的关键步骤。此外，对抑制JIA患者易感型血细胞中PARP-1活性的方法的研究可能最终有助于纠正他们的IL-10产生缺陷，从而恢复患者自身控制关节炎炎症的免疫能力。 公共卫生相关性： 相关性阐明PARP-1调节IL-10基因表达的分子机制将使我们能够确定调节途径中的关键步骤，这些步骤可能被探索为幼年型关节炎治疗干预的潜在靶点。此外，对抑制关节炎患者血细胞中PARP-1活性的方法的研究可能最终有助于纠正他们的IL-10产生缺陷，从而恢复患者自身控制关节炎炎症的免疫能力。

DESCRIPTION (provided by applicant): ABSTRACT: Juvenile idiopathic arthritis (JIA) is the most common chronic autoimmune inflammatory disease in childhood. Lower IL-10 production in patients with the -1082A/-819T/-592A (ATA) IL-10 promoter genotype can lead to excessive inflammatory responses with more severe arthritis, suggesting a direct association of IL-10 gene variants with JIA. Recently, we identified poly(ADP-ribose) polymerase 1 (PARP-1) as a novel transcriptional repressor of IL-10 gene expression with enhanced binding affinity for the ATA IL-10 promoter genotype. Therefore, we hypothesize that PARP-1-mediated suppression of IL-10 production is important for the pathogenesis of JIA, and that removing this suppression could result in effective therapies for treating patients with JIA. IL-10 is a pleiotropic cytokine produced by a variety of immune cells including T cells, B cells, macrophages and dendritic cells. It inhibits the production of proinflammatory cytokines and suppresses the effects of proinflammatory cytokines such as tumor necrosis factor-a (TNF-a). PARP-1 is a highly conserved nuclear zinc- finger protein involved in DNA repair, chromatin decondensation and gene expression. Our recent work has demonstrated that PARP-1 binding to the IL-10 promoter is enhanced by the -592A sequence polymorphism, and that over-expression of PARP-1 results in lower IL-10 production in human macrophages. However, the mechanistic details of how IL-10 is regulated by PARP-1 are unknown, and must be elucidated in order to develop new therapies based on targeting PARP-1. Therefore, in this project, we will: (1) elucidate the mechanistic detail of how PARP-1 regulates IL-10 gene expression at the molecular level. (2) develop methods capable of reversing PARP-1-mediated suppression of IL-10 production in JIA patients expressing the ATA IL-10 promoter genotype. This study will enable us to identify key steps in the regulatory pathway that may be explored as potential targets of therapeutic intervention in JIA. Moreover, the proposed investigation into ways to inhibit PARP-1 activity in JIA patients' blood cells of the susceptible type may eventually help correct their IL-10 production deficit, thus restoring the patients' own immune capacity to control arthritic inflammation. PUBLIC HEALTH RELEVANCE: RELEVANCE Elucidation of the molecular mechanisms whereby PARP-1 regulates IL-10 gene expression will enable us identify key steps in the regulatory pathway that may be explored as potential targets of therapeutic intervention in juvenile arthritis. Moreover, the proposed investigation into ways to inhibit PARP-1 activity in arthritis patients' blood cells may eventually help correct their IL-10 production deficit, thus restoring the patients' own immune capacity to control arthritic inflammation.