Characterization of a Novel Anti-inflammatory Biogenic Amine

Abstract

Abstract Tryptophan (Trp) is an essential amino acid whose catabolism generates a cascade of over fifty molecules in a cell-specific manner. Three major Trp metabolic pathways have been described: synthesis of serotonin, synthesis of melatonin and generation of kynurenines. In mammalian cells, 90% of Trp is processed through the kynurenine pathway and kynurenine metabolites are regarded as one of the most powerful mechanism for immune regulation. We recently reported a novel biogenic amine, 3HKA, generated through a still uncharacterized lateral pathway of Trp catabolism. This novel biogenic amine is generated by both professional (Dendritic Cells) and non-professional (Lymphatic Endothelial Cells) antigen presenting cells and, differently from all others Trp metabolites, display unique “in vivo” immunosuppressive capabilities. In vitro, 3-HKA exhibited an anti-inflammatory profile by inhibiting the IFN-g-mediated STAT1/NF-kB pathway in both mouse and human dendritic cells (DCs) with a consequent decrease in the release of pro-inflammatory chemokines and cytokines; most notably, TNFa, IL-6, and IL12p70. In vivo, 3-HKA exerted protective effects in an experimental mouse model of Psoriasis by decreasing skin thickness, erythema, scaling and fissuring, reducing TNFa, IL-1b, IFN-g, and IL-17 production, and inhibiting generation of effector CD8+ T cells. Similarly, in a mouse model of nephrotoxic nephritis, besides reducing inflammatory cytokines, 3-HKA improved proteinuria and serum urea nitrogen, overall ameliorating the immune-mediated glomerulonephritis and renal dysfunction. Overall we propose that this novel biological amine is a crucial component of Trp-mediated immune tolerance.