Monitoring tryptophan metabolism in chronic immune activation

Abstract

The essential amino acid tryptophan is a constituent of proteins and is also a substrate for two important biosynthetic pathways: the generation of neurotransmitter 5-hydroxytryptamine (serotonin) by tryptophan 5-hydroxylase, and the formation of kynurenine derivatives and nicotinamide adenine dinucleotides. The latter pathway is initiated by the enzymes tryptophan pyrrolase (tryptophan 2,3-dioxygenase, TDO) and indoleamine 2,3-dioxygenase (IDO). TDO is located in liver cells, whereas IDO is expressed in a variety of cells including monocyte-derived macrophages and dendritic cells and is preferentially induced by Th1-type cytokine interferon-γ. Tryptophan depletion via IDO is part of the cytostatic and antiproliferative activity mediated by interferon-γ in cells. In vivo tryptophan concentration can be measured by HPLC by monitoring its natural fluorescence (285 nm excitation and 365 nm emission wavelength). IDO activity is characterized best by the kynurenine to tryptophan ratio which correlates with concentrations of immune activation markers such as neopterin. Low serum/plasma tryptophan concentration is observed in infectious, autoimmune, and malignant diseases and disorders that involve cellular (Th1-type) immune activation as well as during pregnancy due to accelerated tryptophan conversion. Thus, in states of persistent immune activation, low tryptophan concentration may contribute to immunodeficiency. Decreased serum tryptophan can also effect serotonin biosynthesis and thus contribute to impaired quality of life and depressive mood. As such, monitoring tryptophan metabolism in chronic immunopathology provides a better understanding of the association between immune activation and IDO and its role in the development of immunodeficiency, anemia and mood disorders.