Mechanisms of Immune Modulation by Abscisic Acid

描述（由申请人提供）：脱落酸（阿坝）是一种参与调节植物生长的植物物质，也是一种有前途的免疫调节剂。阿坝激活过氧化物酶体增殖物激活受体？(PPAR ??)在报告基因测定中，并在体内调节免疫功能和炎症。本申请的长期目标是阐明阿坝调节免疫功能的细胞和分子机制。具体目标1将测试的假设，阿坝调节淋巴细胞增殖通过过氧化物酶体增殖反应？- 依赖机制。为了验证这一假设，我们将：1）调查阿坝的异构体和对映体激活过氧化物酶体增殖体激活受体的能力？在Jurkat细胞的报告分析; 2）评估的特异性纯阿坝对映体的过氧化物酶体受体？配体结合试验; 3）使用最有效的过氧化物酶体增殖物激活受体？- 激活对映体的机制研究，在体内，以确定是否表达的过氧化物酶体增殖物激活受体？在免疫细胞中，阿坝对流感病毒疫苗接种小鼠的免疫调节作用是必需的;和4）研究阿坝对流感病毒疫苗接种的抗原特异性T细胞应答的作用是否继发于巨噬细胞来源的PGE 2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导致宿主衰弱。有趣的是，阿坝抑制巨噬细胞MCP-1 mRNA和蛋白质的表达。核因子-？B（NF-？B）是MCP-1转录的中心诱导物。具体目标2将测试阿坝通过一个过氧化物酶体增殖物激活受体下调单核细胞趋化蛋白-1产生的假设。介导的NF-？B。具体目标2将剖析阿坝对MCP-1表达的转录调控机制。具体而言，我们将：1）确定阿坝处理对NF-？探讨阿坝是否抑制NF-？B亚基或诱导I？B？炎症条件下的表达; 3）评估ABA激活的PPAR？和RelA及其在抑制巨噬细胞中MCP-1表达中的作用;和4）确定阿坝是否通过激活PPAR？抑制NF-？B。对植物性药物如阿坝的免疫调节特性的机理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.