5 -Hydroxytryptophan Regulation of Endothelial Cell Signals for Lung Inflammation

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DESCRIPTION (provided by applicant): The prevalence of asthma and allergic diseases has dramatically increased in the last 40 years. Therefore, it is critical to determine mechanisms for regulation of allergy/asthma in order to identify novel targets for intervention. We recently demonstrated that 5-hydroxytryptophan (5HTP) supplementation inhibits allergic lung inflammation and allergen-induced airway hyperresponsiveness (AHR). Cells metabolize 5HTP to serotonin but many reports indicate that 5HTP and serotonin administration have opposite outcomes on physiological responses. Reduced synthesis of 5HTP is associated with anxiety/depression. Interestingly, there are many clinical reports indicating an association of anxiety/depression with allergy/asthma, but the mechanism for this association is not known. It is also reported that anxiety is increased in rodents challenged with allergen, suggesting a potential coordinated regulation. We propose a novel concept that leukocyte recruitment and anxiety/depression during allergy/asthma are coordinately reduced by 5HTP supplementation. 5HTP is metabolized to serotonin and then serotonin binds inhibitory or stimulatory serotonin receptors (HTRs) or serotonin is covalently linked to proteins (serotonylation). Consistent with our novel concept, we reported that 5HTP reduced allergic inflammation, decreased allergen-induced serotonylation in endothelial cells and reduced allergen-induced AHR. In vitro, 5HTP-pretreatment of endothelial cells blocked leukocyte transendothelial migration and blocked cytokine-stimulated endothelial cell serotonylation, suggesting a negative feedback regulation by 5HTP. Our long-term goal is to identify mechanisms for 5HTP regulation of leukocyte recruitment in allergy/asthma and thus identify potential targets for intervention in allergic inflammation and the associated anxiety/depression symptoms. As a step towards our long-term goal, our central hypothesis is that the readily available amino acid supplement 5HTP (from the plant Griffonia Simplifolia) limits leukocyte recruitment through 5HTP inhibition of endothelial cell signals and consequently eosinophil-dependent AHR and allergen-induced anxiety. We will test our central hypothesis with the following specific aims: Aim 1. Test the hypothesis that HTRs on endothelial cells and/or leukocytes mediate 5HTP inhibition of leukocyte transendothelial migration in vitro. Aim 2. Test the hypothesis that 5HTP inhibits VCAM-1 intracellular signals in endothelial cells during VCAM-1-dependent leukocyte transendothelial migration in vitro. Aim 3. Test the hypothesis that 5HTP inhibits leukocyte recruitment, AHR and the associated antigen-induced elevation of anxiety through 5HTP regulation of HTRs or serotonylation. It is anticipated that the aims will identify mechanisms for 5HTP inhibition of allergic inflammation, allergen-induced AHR and anxiety. Such results are expected to have an important positive impact, because it is likely that new targets for intervention will be determined in addition to advancing the mechanistic understanding of 5HTP regulation of inflammation.