Molecular Regulation of Inflammatory Cytokine Production in Macrophages

巨噬细胞炎症细胞因子产生的分子调控

• 批准号: RGPIN-2018-06053
• 负责人: Uzonna, Jude
• 金额: $ 3.06万
• 依托单位: University of Manitoba
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=667422
• 关键词: Molecular; Regulation; Inflammatory; Cytokine; Production

***Background: An important function of the immune system is to initiate inflammatory response that is required to control insults and initiate tissue repair. The inflammatory process is normally self-limiting and regulated in order to avoid collateral tissue-damage. A dysregulation of inflammation results in excessive and persistent inflammation, which is characterized by elevated expression of proinflammatory cytokines. Myeloid immune cells (particularly macrophages and neutrophils) play important roles in inflammation via their production of inflammatory mediators including cytokines. The molecular mechanisms controlling inflammation have not been fully delineated.******Recently, we showed that Diminazene aceturate (Berenil, which is an aromatic diamidine), inhibits IL-1, IL-6, IL-12 and TNF production by macrophages in vivo and in vitro following stimulation with Trypanosoma congolense, lipopolysaccharide (LPS) and CpG. We recently in preliminary studies validated these findings using newer and safer diamidine compounds. This global suppressive effect was due to downregulation of phosphorylation of mitogen-activated protein kinases (MAPKs, including ERK, p38 and JNK), signal transducer and activator of transcription (STAT) proteins (STAT1 and STAT3) and NFκB p65 subunit, which are key signaling molecules and transcription factors involved in the production of proinflammatory cytokines. Berenil also increases neutrophil numbers in lungs, blood and peritoneal lavage fluids following LPS challenge. The molecular mechanisms through which Berenil mediates increased neutrophil survival and/or number is unknown. ******The overarching goal of the current renewal application is to identify trypanosome molecule(s) that induce inflammatory cytokines and determine molecular mechanisms by which Berenil regulates inflammatory cytokine production by macrophages and neutrophils in vitro and in vivo. The objectives are: (i) to dissect the molecules and mechanisms through trypanosomes induce proinflammatory cytokines (Project 1), (ii) determine molecular mechanisms through which Berenil suppresses proinflammatory cytokine production in macrophages (Project 2) and (iii) determine whether Berenil increases neutrophil survival, recruitment and/or mobilization from the bone marrow by assessing markers of apoptosis in neutrophils from various tissue (Project 3). ******Significance: The proposed studies will establish the mechanistic processes involved in the anti-inflammatory properties of Berenil. The long-term vision is to have a broad and in-depth understanding of mechanisms that regulate inflammatory responses, which may reveal novel ways of targeting inflammatory conditions. The novelty of the research project and the cutting edge technologies involved will continue to create a rich environment for the training of HQP (2-3 graduate and 5 undergraduate students). **

* 背景：免疫系统的一个重要功能是启动控制损伤和启动组织修复所需的炎症反应。炎症过程通常是自我限制和调节的，以避免附带的组织损伤。炎症的失调导致过度和持续的炎症，其特征在于促炎细胞因子的表达升高。髓样免疫细胞（特别是巨噬细胞和嗜中性粒细胞）通过其产生包括细胞因子的炎性介质在炎症中起重要作用。控制炎症的分子机制尚未完全阐明。最近，我们发现乙酰二氨基苯乙酸酯（Berenil，其为芳香族联脒）在体内和体外用刚果锥虫、脂多糖（LPS）和CpG刺激后抑制巨噬细胞产生IL-1、IL-6、IL-12和TNF。我们最近在初步研究中使用更新和更安全的联脒化合物验证了这些发现。这种全面的抑制作用是由于下调了丝裂原活化蛋白激酶（MAPK，包括ERK、p38和JNK）、信号转导和转录激活因子（STAT）蛋白（STAT 1和STAT 3）以及NFκB p65亚基的磷酸化，这些蛋白是参与促炎细胞因子产生的关键信号分子和转录因子。Berenil还增加LPS激发后肺、血液和腹膜灌洗液中的中性粒细胞数量。Berenil介导增加中性粒细胞存活和/或数量的分子机制尚不清楚。** 当前更新申请的首要目标是鉴定诱导炎性细胞因子的锥虫分子，并确定Berenil在体外和体内调节巨噬细胞和中性粒细胞产生炎性细胞因子的分子机制。其目标是：（i）剖析通过锥虫诱导促炎性细胞因子的分子和机制（项目1），（ii）确定Berenil抑制巨噬细胞中促炎性细胞因子产生的分子机制（项目2）和（iii）通过评估来自各种组织的中性粒细胞中的凋亡标志物来确定Berenil是否增加中性粒细胞存活、从骨髓的募集和/或动员（项目3）。** 重要性：拟议的研究将建立Berenil抗炎特性中涉及的机制过程。长期愿景是对调节炎症反应的机制有广泛而深入的了解，这可能揭示靶向炎症条件的新方法。该研究项目的新奇和所涉及的尖端技术将继续为HQP（2-3名研究生和5名本科生）的培训创造丰富的环境。**