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. ? ? ?
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