A deficiency of dietary protein or amino acids has long been known to impair immune function and increase the susceptibility of animals and humans to infectious disease. However, only in the past 15 years have the underlying cellular and molecular mechanisms begun to unfold. Protein malnutrition reduces concentrations of most amino acids in plasma. Findings from recent studies indicate an important role for amino acids in immune responses by regulating: (1) the activation of T lymphocytes, B lymphocytes, natural killer cells and macrophages; (2) cellular redox state, gene expression and lymphocyte proliferation; and (3) the production of antibodies, cytokines and other cytotoxic substances. Increasing evidence shows that dietary supplementation of specific amino acids to animals and humans with malnutrition and infectious disease enhances the immune status, thereby reducing morbidity and mortality. Arginine, glutamine and cysteine precursors are the best prototypes. Because of a negative impact of imbalance and antagonism among amino acids on nutrient intake and utilisation, care should be exercised in developing effective strategies of enteral or parenteral provision for maximum health benefits. Such measures should be based on knowledge about the biochemistry and physiology of amino acids, their roles in immune responses, nutritional and pathological states of individuals and expected treatment outcomes. New knowledge about the metabolism of amino acids in leucocytes is critical for the development of effective means to prevent and treat immunodeficient diseases. These nutrients hold great promise in improving health and preventing infectious diseases in animals and humans.

https://www.cambridge.org/core/services/aop-cambridge-core/content/view/B1A9C1587A8602613F6447BA8404D8E1/S000711450769936Xa.pdf/div-class-title-amino-acids-and-immune-function-div.pdf

Amino acids and immune function

Picolinic acid, a catabolite of L-tryptophan, activates the transcription of the inducible nitric oxide synthase gene (iNOS) in IFN-gamma-treated murine macrophages. We performed functional studies on the 5' flanking region of the iNOS gene linked to a CAT reporter gene to identify the cis-acting element(s) responsible for the activation of iNOS transcription by picolinic acid. Transient transfection assays showed that the full-length iNOS promoter in the murine macrophage cell line ANA-1 was activated by the synergistic interaction between IFN-gamma and picolinic acid. Deletion or mutation of the iNOS promoter region from -227 to -209, containing a sequence homology to a hypoxia-responsive enhancer (iNOS-HRE), decreased picolinic acid- but not LPS-induced CAT activity by more than 70%. Functional studies using a tk promoter-CAT reporter gene plasmid demonstrated that the iNOS-HRE was sufficient to confer inducibility by picolinic acid but not by IFN-gamma or LPS. Electrophoretic mobility shift assays confirmed that picolinic acid alone induced a specific binding activity to the iNOS-HRE. Furthermore, we found that the iNOS-HRE activity was inducible by hypoxia and that hypoxia in combination with IFN-gamma activated the iNOS promoter in transient transfection assays and induced iNOS transcription and mRNA expression. These data establish that the iNOS-HRE is a novel regulatory element of the iNOS promoter activity in murine macrophages and provide the first evidence that iNOS is a hypoxia-inducible gene.

https://rupress.org/jem/article-pdf/182/6/1683/1107335/1683.pdf

A hypoxia-responsive element mediates a novel pathway of activation of the inducible nitric oxide synthase promoter.

Regulatory and functional aspects of the kynurenine (K) pathway (KP) of tryptophan (Trp) degradation are reviewed. The KP accounts for ~95% of dietary Trp degradation, of which 90% is attributed to the hepatic KP. During immune activation, the minor extrahepatic KP plays a more active role. The KP is rate-limited by its first enzyme, Trp 2,3-dioxygenase (TDO), in liver and indoleamine 2,3-dioxygenase (IDO) elsewhere. TDO is regulated by glucocorticoid induction, substrate activation and stabilization by Trp, cofactor activation by heme, and end-product inhibition by reduced nicotinamide adenine dinucleotide (phosphate). IDO is regulated by IFN-γ and other cytokines and by nitric oxide. The KP disposes of excess Trp, controls hepatic heme synthesis and Trp availability for cerebral serotonin synthesis, and produces immunoregulatory and neuroactive metabolites, the B3 "vitamin" nicotinic acid, and oxidized nicotinamide adenine dinucleotide. Various KP enzymes are undermined in disease and are targeted for therapy of conditions ranging from immunological, neurological, and neurodegenerative conditions to cancer.

https://journals.sagepub.com/doi/pdf/10.1177/1178646917691938

Kynurenine Pathway of Tryptophan Metabolism: Regulatory and Functional Aspects

This paper reviews the body of evidence that not only tryptophan and consequent 5-HT depletion, but also induction of indoleamine 2,3-dioxygenase (IDO) and the detrimental effects of tryptophan catabolites (TRYCATs) play a role in the pathophysiology of depression. IDO is induced by interferon (IFN)γ, interleukin-6 and tumor necrosis factor-α, lipopolysaccharides and oxidative stress, factors that play a role in the pathophysiology of depression. TRYCATs, like kynurenine and quinolinic acid, are depressogenic and anxiogenic; activate oxidative pathways; cause mitochondrial dysfunctions; and have neuroexcitatory and neurotoxic effects that may lead to neurodegeneration. The TRYCAT pathway is also activated following induction of tryptophan 2,3-dioxygenase (TDO) by glucocorticoids, which are elevated in depression. There is evidence that activation of IDO reduces plasma tryptophan and increases TRYCAT synthesis in depressive states and that TDO activation may play a role as well. The development of depressive symptoms during IFNα-based immunotherapy is strongly associated with IDO activation, increased production of detrimental TRYCATs and lowered levels of tryptophan. Women show greater IDO activation and TRYCAT production following immune challenge than men. In the early puerperium, IDO activation and TRYCAT production are associated with the development of affective symptoms. Clinical depression is accompanied by lowered levels of neuroprotective TRYCATs or increased levels or neurotoxic TRYCATs, and lowered plasma tryptophan, which is associated with indices of immune activation and glucocorticoid hypersecretion. Lowered tryptophan and increased TRYCATs induce T cell unresponsiveness and therefore may exert a negative feedback on the primary inflammatory response in depression. It is concluded that activation of the TRYCAT pathway by IDO and TDO may be associated with the development of depressive symptoms through tryptophan depletion and the detrimental effects of TRYCATs. Therefore, the TRYCAT pathway should be a new drug target in depression. Direct inhibitors of IDO are less likely to be useful drugs than agents, such as kynurenine hydroxylase inhibitors; drugs which block the primary immune response; compounds that increase the protective effects of kynurenic acid; and specific antioxidants that target IDO activation, the immune and oxidative pathways, and 5-HT as well.

The new '5-HT' hypothesis of depression: cell-mediated immune activation induces indoleamine 2,3-dioxygenase, which leads to lower plasma tryptophan and an increased synthesis of detrimental tryptophan catabolites (TRYCATs), both of which contribute to the onset of depression.

Monitoring tryptophan metabolism in chronic immune activation.

The antiproliferative effects of interferon alpha (IFN-alpha) and interferon gamma (IFN-gamma) were found to be cell-dependent. Among the human cell lines examined, IFN-gamma had a greater antiproliferative effect against cell lines that exhibited induction of indoleamine 2,3-dioxygenase, such as the KB oral carcinoma or WiDr colon adenocarcinoma, than against those that lacked the enzyme activity, such as the SW480 colon adenocarcinoma or NCI-H128 small-cell lung carcinoma. Induction of this dioxygenase showed a clear temporal relationship with increased metabolism of L-tryptophan and the depletion of this amino acid in the culture medium. While 70-80% of L-tryptophan remained in the medium of IFN-alpha- or vehicle-treated cells, virtually all of this amino acid was depleted in the medium of the IFN-gamma-treated group following 2-3 days of culture. Supplementing the growth medium with additional L-tryptophan reversed the antiproliferative effect of IFN-gamma against KB cells in a dose- and time-dependent manner. The antiproliferative effects of IFN-alpha and IFN-gamma on SW480 and NCI-H128 cells, which are independent of the dioxygenase activity, and the inability of added L-tryptophan to reverse the effects of IFN-gamma in WiDr cells suggest multiple mechanisms of action of the IFNs. The data show that the antiproliferative effect of IFN-gamma through induction of indoleamine 2,3-dioxygenase, with a consequent L-tryptophan deprivation, is an effective means of regulating cell growth.

https://www.pnas.org/content/pnas/85/4/1242.full.pdf

Induction of indoleamine 2,3-dioxygenase: a mechanism of the antitumor activity of interferon gamma

The actions of interferon and antiinflammatory agents on induction of indoleamine 2,3-dioxygenase in human peripheral blood monocytes

Cofactor activity of dihydroflavin mononucleotide and tetrahydrobiopterin for murine epididymal indoleamine 2,3-dioxygenase

The antiproliferative effects of interferon a (IFN-a) and interferon y (IFN-y) were found to be cell- dependent. Among the human cell lines examined, IFN-y had a greater antiproliferative effect against cell lines that exhib- ited Induction of indoleamine 2,3-dioxygenase, such as the KB oral carcinoma or WiDr colon adenocarcinoma, than against those that lacked the enzyme activity, such as the SW480 colon adenocarcinoma or NCI-H128 small-cell lung carcinoma. In- duction of this dioxygenase showed a clear temporal relation- ship with increased metabolism of L-tryptophan and the depletion of this amino acid in the culture medium. While 70-80% of L-tryptophan remained in the medium of IFN-a- or vehicle-treated cells, virtually all of this amino acid was depleted in the medium of the IFN-y-treated group following 2-3 days of culture. Supplementing the growth medium with additional L-tryptophan reversed the antiproliferative effect of IFN-y against KB cells in a dose- and time-dependent manner. The antiproliferative effects of IFN-a and IFN-y on SW480 and NCI-H128 cells, which are independent of the dioxygenase activity, and the inability of added L-tryptophan to reverse the effects of IFN-y in WiDr cells suggest multiple mechanisms of action of the IFNs. The data show that the antiproliferative effect of IFN-y through induction of indoleamine 2,3- dioxygenase, with a consequent L-tryptophan deprivation, is an effective means of regulating cell growth.

Induction of indoleamine 2,3-dioxygenase: A mechanism of the antitumor activity of interferon y (cell proliferation/L-tryptophan/amino acid metabolism/neoplastic cells/cel culture)

Yoshisuke Ozaki

Papers

Induction of indoleamine 2,3-dioxygenase: a mechanism of the antitumor activity of interferon gamma

The actions of interferon and antiinflammatory agents on induction of indoleamine 2,3-dioxygenase in human peripheral blood monocytes

Cofactor activity of dihydroflavin mononucleotide and tetrahydrobiopterin for murine epididymal indoleamine 2,3-dioxygenase

Induction of indoleamine 2,3-dioxygenase: A mechanism of the antitumor activity of interferon y (cell proliferation/L-tryptophan/amino acid metabolism/neoplastic cells/cel culture)