Dr. Ron’s Research Review – February 8, 2017

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This week’s research review focuses on tryptophan and the immune system.

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. (Schröcksnadel et al., 2006)

Tryptophan (Trp) degradation may be a potent immunosuppressive mechanism involved in the maintenance of immunological tolerance. Both tryptophan depletion and downstream tryptophan catabolites (TCs) appear to synergistically confer protection against excessive inflammation. (Opitz et al., 2007)

Immune deviations that are most widely expressed in the elderly include increased neopterin production and tryptophan breakdown. These biochemical events result from the activation of the immune system and are preferentially triggered by pro-inflammatory stimuli, such as the Th1-type cytokine interferon-γ. Concentrations of the biomarkers neopterin and Kyn/Trp were found to be predictive of overall disease specific mortality in coronary artery disease, infections and various types of cancer. (Capuron et al., 2014)

Dr. Ron


 

Articles

Activated immune system and inflammation in healthy ageing: relevance for tryptophan and neopterin metabolism.
            (Capuron et al., 2014) Download
Immune activation not only accompanies inflammation in various disorders including infections, autoimmune syndromes and cancer, but it also represents a characteristic feature of ageing. Immune deviations which are most widely expressed in the elderly include increased neopterin production and tryptophan breakdown. These biochemical events result from the activation of the immune system and are preferentially triggered by pro-inflammatory stimuli, such as the Th1-type cytokine interferon-γ. They seem to play a role in the development of several age-related disorders and might be involved in the pathogenesis of common symptoms, including neurobehavioral disorders (e.g., cognitive and mood disturbances), anemia, cachexia, weight-loss but also immunodeficiency. Concentrations of the biomarkers neopterin and Kyn/Trp were found to be predictive of overall disease specific mortality in coronary artery disease, infections and various types of cancer. Immune activation and inflammation are also accompanied by high output of reactive oxygen species and thereby may lead to the development of oxidative stress and contribute to the vitamin deficiency which is often observed in the elderly. Accordingly, increases in neopterin were found to correlate with a substantial decline in key vitamins, including folate and vitamin-B6, - B12, -C, -D and -E.

Tryptophan degradation in autoimmune diseases.
            (Opitz et al., 2007) Download
Recent evidence points to tryptophan (Trp) degradation as a potent immunosuppressive mechanism involved in the maintenance of immunological tolerance. Both Trp depletion and downstream Trp catabolites (TCs) appear to synergistically confer protection against excessive inflammation. In this review, we give an overview of the immunosuppressive properties of Trp degradation with special focus on TCs. Constitutive and inducible Trp degradation in different cell types and tissues of human and murine origin is summarized. We address the influence of Trp degradation on different aspects of autoimmune disorders such as multiple sclerosis. Possible therapeutic approaches for autoimmune disorders targeting Trp degradation are presented, and key issues relevant for the development of such therapeutic strategies are discussed.


 

Monitoring tryptophan metabolism in chronic immune activation.
            (Schröcksnadel et al., 2006) Download
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-gamma. Tryptophan depletion via IDO is part of the cytostatic and antiproliferative activity mediated by interferon-gamma 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.

 

References

Capuron, L, et al. (2014), ‘Activated immune system and inflammation in healthy ageing: relevance for tryptophan and neopterin metabolism.’, Curr Pharm Des, 20 (38), 6048-57. PubMed: 24641220
Opitz, CA, et al. (2007), ‘Tryptophan degradation in autoimmune diseases.’, Cell Mol Life Sci, 64 (19-20), 2542-63. PubMed: 17611712
Schröcksnadel, K, et al. (2006), ‘Monitoring tryptophan metabolism in chronic immune activation.’, Clin Chim Acta, 364 (1-2), 82-90. PubMed: 16139256