Furthermore, as Trp is also involved in neurological functions as a precursor in the synthesis of serotonin, a neurotransmitter that modulates mood, cognition and several neuroendocrine rhythms , the kynurenine pathway appears to compete with the serotoninergic pathway for Trp availability. An increase in IDO activity consequently imbalances the kynurenine/serotonin pathways, thus resulting in a decrease of serotonin synthesis and an accumulation of kynurenine metabolites, most of them displaying neuroactive properties . Accordingly, changes in peripheral and/or central serotonin and kynurenine metabolites concentrations have been shown to be involved in several neurodegenerative disorders, such as Alzheimer��s and Parkinson��s diseases, as well as in mental illnesses, such as schizophrenia and depression . Additionally, IFN-alpha-induced activation of IDO is regarded as being responsible for neuropsychiatric side effects, such as anxiety and major depression, which can develop in patients chronicallytreated by IFN-a immunotherapy, and trigger non-compliance or premature discontinuation of treatment . Although the role of IDO and its induction by cytokines are now well recognized, not many studies have focused on the mechanisms of variability of IDO activity, which could have numerous relevant 154447-36-6 clinical implications. In vitro studies have shown that the response of IDO to IFN-c stimulation varies greatly between various human cell lines . Based on the kynurenine/tryptophan ratio, which is calculated from circulating concentrations and is recognized as a valid indicator of IDO activity , it appears that IDO activity exhibits relatively large interindividual variability, in particular in pathological conditions . Indirect evidence of interindividual variability in IDO activity, and/or inductibility, is also supported by several studies that showed that the development of IFN-a-induced neuropsychiatric symptoms only occurs in 20�C50% of cancer- or hepatitis Ctreated patients . The currently known causes of variation in IDO activity remain sparse. Physiological states such as ageing or pregnancy, as well as pathological conditions such as infection, inflammation or tumor proliferation, have been demonstrated to modify IDO expression and/or activity, but they all GDC-0941 biological activity mainly reflect the various mechanisms involved in the regulation of IDO expression .