Mechanisms of Immune Modulation by Abscisic Acid

描述(申请人提供)：脱落酸(ABA)是一种参与植物生长调节的植物学物质，也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？？)在报告中分析和调节体内的免疫功能和炎症。这一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。具体目标1将验证ABA通过依赖PPAR？的机制调节淋巴细胞增殖的假设。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细胞的报告实验中；2)评价纯ABA对映体作为PPAR？3)利用最有效的PPAR？激活对映体进行体内机制研究，以确定PPAR？ABA在免疫细胞中的免疫调节作用是必需的；以及4)研究ABA对流感病毒疫苗接种后抗原特异性T细胞反应的影响是否次于抑制巨噬细胞衍生的PGE2。单核细胞趋化蛋白-1(MCP-1)是一种趋化因子，在流感病毒感染过程中参与宿主的衰弱作用。有趣的是，ABA抑制巨噬细胞MCP-1mRNA和蛋白的表达。核因子-β是单核细胞趋化蛋白-1转录的中枢诱导物。特异靶2将验证这样的假设，即ABA通过PPAR？介导的对核因子-βB的阻断而下调MCP-1的产生。特异靶2将剖析ABA对MCP-1表达的转录调控机制。具体地说，我们将：1)确定ABA处理对巨噬细胞中NF-B的DMA结合活性的影响；2)研究ABA在炎症条件下是否抑制NF-B亚单位的表达或诱导I？B？表达；3)评估ABA激活的PPAR？和RERA及其在抑制巨噬细胞MCP-1表达中的作用；4)确定ABA是否通过激活PPAR来抑制流感病毒感染小鼠的肺部炎症病理和MCP-1表达？从机理上了解ABA等植物药物的免疫调节特性将有助于开发更有效的CAM方法来调节免疫功能和改善感染性疾病。

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.