Kynurenine versus serotonergic pathway: role in the cross talking of immune cells and in the immune escape of tumors

Abstract

The metabolism of tryptophan (TRP) is driven by the kynurenine (KYN) and the serotonergic (SER) pathways. The first generates Kynurenine (KYN) and a range of secondary products and, when carry out by the enzyme indoleamine 2,3 dioxygenase (IDO) contributes to immune tolerance and escape of tumor cells. The SER pathway leads to the production of serotonin (5-HT), which can generate melatonin (MLT) and other metabolites. The products of the SER pathway, as well as MLT and metabolites have immunomodulatory effects and there is evidences suggesting that compounds from these pathways control tumor growth. It has been shown that different types of tumors and cells of the immune system express IDO. Given the importance of the KYN pathway in the evaluation of severity and in the development of antineoplastic therapies, the objective of this study is to identify the importance of the KYN and SER pathways in TRP metabolism in monocytes, macrophages, dendritic cells, lymphocytes and some human tumor lineages. The activation of these routes will be evaluated also upon treatment of cultured cells with IFN-g. Although IFN-g is a classic inducer of the KYN pathway, its effect on SER pathway is not known. From the mapping of the KYN and SER routes in the different cell types that will be assayed in this study, we will know whether these routes were simultaneously activated or competitive. Some preliminary studies from our lab in free cell system support the participation of metabolites of both paths in regulation. Our hypothesis are that the KYN and SER pathways affects each other, that the SER pathway generates products that modulates the immune response, and that, besides the KYN path, also the SER path could define tumor progression. With co-cultures experiments we will evaluate the impact of TRP metabolism paths in the cross-talking between tumor and immune cells. (AU)