The kynurenine pathway is a fundamental mechanism of immunosuppression and peripheral tolerance. It is increasingly recognized as playing a major role in the pathogenesis of a wide variety of inflammatory, neurodegenerative and malignant disorders. However, the temporal dynamics of kynurenine pathway activation and metabolite production in human immune cells is currently unknown. Here we report the novel use of flow cytometry, combined with ultra high-performance liquid chromatography and gas chromatography-mass spectrometry, to sensitively quantify the intracellular expression of three key kynurenine pathway enzymes and the main kynurenine pathway metabolites in a time-course study. This is the first study to show that up-regulation of indoleamine 2,3-dioxygenase (IDO-1), kynurenine 3-monoxygenase (KMO) and quinolinate phosphoribosyltransferase (QPRT) is lacking in lymphocytes treated with interferon gamma. In contrast, peripheral monocytes showed a significant elevation of kynurenine pathway enzymes and metabolites when treated with interferon gamma. Expression of IDO-1, KMO and QPRT correlated significantly with activation of the kynurenine pathway (kynurenine:tryptophan ratio), quinolinic acid concentration and production of the monocyte derived, pro-inflammatory immune response marker: neopterin. Our results also describe an original and sensitive methodological approach to quantify kynurenine pathway enzyme expression in cells. This has revealed further insights into the potential role of these enzymes in disease processes.
Adolescence has been described as an important period to acquire social competences required for adult life. It has been suggested that early stress experiences could affect the development of the brain at different levels. These changes in the brain during adolescence may be related with the development of psychopathologies such as depression and social anxiety in adulthood. In the first experiment, we examined long-term effects of repeated social stress during adolescence on adult social approach-avoidance behavior. For that purpose, adolescent male Wistar rats were exposed twice at postnatal day (Pnd) 45 and Pnd48 to the resident-intruder paradigm followed by three times psychosocial threat with the same resident. Three weeks after the last psychosocial threat experience the animals were behaviorally tested in a social approach-avoidance test. Socially stressed animals spent less time in the interaction zone with an unfamiliar male adult rat. These data suggest that animals exposed to social stress during adolescence show a higher level of social anxiety in adulthood. In the second experiment, we investigated whether these long-term effects of social stress during adolescence on behavior draw a parallel with changes in brain monoamine content, biosynthesis and turnover. Using the same experimental design as in the first experiment, HPLC analysis of various brain regions showed that there were no differences in monoamine content, monoamine biosynthesis and monoamines activity in the prefrontal cortex, hippocampus, hypothalamus and striatum in adulthood. These results indicate that long-lasting changes in social behavior following social stress during adolescence are not accompanied by changes in brain monoamine content, biosynthesis and turnover.
Age is considered a dominant risk factor in the development of most neurodegenerative disorders. The kynurenine pathway, a major metabolic pathway of tryptophan is altered in the majority of neurodegenerative disorders. In this study, we have analysed CSF samples from 49 healthy women across a wide age range (0-90) for kynurenine pathway metabolites and the inflammatory marker neopterin. Our results show central tryptophan metabolism is increased with age in women, with an apparent shift towards the neurotoxin quinolinic acid. We also observed an increase in central levels of the inflammatory marker neopterin with age and a positive correlation between neopterin and kynurenine pathway activation. We conclude that, the changes that occur in the kynurenine pathway as a result of normal ageing are mechanistically linked to increased inflammatory signalling and have some explanatory potential with regard to ageassociated degenerative diseases in the CNS. Management of health in ageing and (preventative) treatment would do well to look to the kynurenine pathway for potentially novel solutions.
Schizophrenia has a clear sexual dimorphism in age of onset and progression. The underlying mechanisms of this dimorphism are not known, but may be found in the interactions of sex hormones with the tryptophan catabolising kynurenine pathway. Schizophrenia is associated with general inflammation and disruption of glutamatergic and dopaminergic signalling. Metabolites of the kynurenine pathway have been shown to be immunomodulatory and have effects on glutamatergic and dopaminergic signalling. This review discusses the currently available literature on sex hormones and their effect on the kynurenine pathway in the context of the glutamatergic, dopaminergic and immunological features of schizophrenia.
We have previously demonstrated that the kynurenine pathway (KP), the major biochemical pathway for tryptophan metabolism, is dysregulated in many inflammatory disorders that are often associated with sexual dimorphisms. We aimed to identify a potential functional interaction between the KP and gonadal hormones. We have treated primary human macrophages with progesterone in the presence and absence of inflammatory cytokine interferon-gamma (interferon-γ) that is known to be a potent inducer of regulating the KP enzyme. We found that progesterone attenuates interferon-γ-induced KP activity, decreases the levels of the excitotoxin quinolinic acid, and increases the neuroprotective kynurenic acid levels. We also showed that progesterone was able to reduce the inflammatory marker neopterin. These results may shed light on the gender disparity in response to inflammation.
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