Mechanisms of Immune Modulation by Abscisic Acid

描述（申请人提供）：脱落酸（ABA）是一种植物性物质，参与调节植物生长，是一种很有前途的免疫调节剂。ABA激活过氧化物酶体增殖物激活受体？？（PPAR ??）在报告细胞中检测并调节体内免疫功能和炎症。本应用的长期目标是阐明ABA调节免疫功能的细胞和分子机制。特异性目的1将检验ABA通过PPAR调节淋巴细胞增殖的假设。端依赖机制。为了验证这一假设，我们将：1)研究ABA的异构体和对映体激活PPAR的能力。在Jurkat细胞报告细胞试验中；2)评价纯ABA对映体作为PPAR的特异性？结合试验中的配体；3)使用最有效的PPAR？-活化对映体进行体内机制研究，以确定PPAR？在流感病毒接种小鼠中，ABA的免疫调节作用需要在免疫细胞中发挥作用；4)研究ABA对流感病毒疫苗免疫后抗原特异性T细胞反应的影响是否继发于巨噬细胞源性PGE2的抑制。单核细胞趋化蛋白-1 （MCP-1）是一种趋化因子，在流感病毒感染期间有助于宿主的衰弱作用。有趣的是，ABA抑制巨噬细胞MCP-1 mRNA和蛋白的表达。核因子- ?B (NF - ?B)是MCP-1转录的中心诱导剂。特异性目标2将检验ABA通过PPAR下调MCP-1产生的假设。介导的NF- B阻断。特异性目的2将剖析ABA对MCP-1表达的转录调控机制。具体而言，我们将：1)测定ABA处理对NF-？巨噬细胞B；2)探讨ABA是否抑制NF-？B亚基还是诱导I?B?？炎症条件下的表达；3)评估aba激活PPAR的物理相互作用？RelA及其在巨噬细胞中抑制MCP-1表达的作用；4) ABA是否通过激活PPAR抑制流感病毒感染小鼠肺部炎症病理和MCP-1表达？抑制NF-?B对植物药物如ABA的免疫调节特性的机制理解将有助于开发更有效的CAM方法来调节免疫功能和改善传染病。

DESCRIPTION (provided by applicant): Abscisic acid (ABA) is a botanical involved in the regulation of plant growth and a promising immune modulator. ABA activates peroxisome proliferator-activated receptor?? (PPAR ??) in reporter assays and modulates immune function and inflammation in vivo. The long-term goal of this application is to elucidate the cellular and molecular mechanisms by which ABA modulates immune function. Specific Aim 1 will test the hypothesis that ABA modulates lymphocyte proliferation through a PPAR? -dependent mechanism. To test this hypothesis we will: 1) Investigate the ability of ABA's isomers and enantiomers to activate PPAR? in reporter assays in Jurkat cells; 2) Evaluate the specificity of pure ABA enantiomers as PPAR? ligands in binding assays; 3) Use the most effective PPAR? -activating enantiomer for mechanistic studies in vivo to determine whether the expression of PPAR? in immune cells is required for ABA's immunoregulatory actions in influenza virus-vaccinated mice; and 4) Investigate whether the effects of ABA on antigen-specific T cell responses to influenza virus vaccination are secondary to suppression of macrophage-derived PGE2. Monocyte chemoattractant protein-1 (MCP-1) is a chemokine that contributes to the debilitating effects in the host during influenza virus infections. Interestingly, ABA suppresses macrophage MCP-1 mRNA and protein expression. Nuclear factor-?B (NF-?B) is a.central inducer of MCP-1 transcription. Specific Aim 2 will test the hypothesis that ABA down-modulates MCP-1 production through a PPAR?-mediated blockade of NF-?B. Specific aim 2 will dissect the mechanisms of transcriptional regulation of MCP-1 expression by ABA. Specifically, we will: 1) Determine the influence of ABA treatment on the DMA-binding activity of NF-?B in macrophages; 2) Investigate whether ABA represses the expression of NF-?B subunits or induces I?B??expression under inflammatory conditions; 3) Assess the physical interaction of ABA-activated PPAR? and RelA and its role in inhibiting MCP-1 expression in macrophages; and 4) Determine if ABA suppresses the pulmonary inflammatory pathology and MCP-1 expression in the lungs of influenza virus-infected mice by activating PPAR? and inhibiting NF-?B. The mechanistic understanding of the immune modulatory properties of botanicals such as ABA will aid in the development of more efficacious CAM approaches for modulating immune function and ameliorating infectious diseases.