Role of Kynurenine Pathway in Infections

Eller, Silvia Kathrin; Däubener, Walter

doi:10.1007/978-3-319-11870-3_14

Cited by 10 publications

(4 citation statements)

References 44 publications

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“…However, we observed that there was no full recovery of T. gondii growth by supplemental tryptophan in hRPE cells pre-treated with high doses of IFN-γ. This might be a hint for the presence of toxic amounts of kynurenine or kynurenine-derived metabolites that affect the parasites, but not S. aureus or host cells [32].…”

Section: Discussionmentioning

confidence: 99%

Interplay between IDO1 and iNOS in human retinal pigment epithelial cells

Spekker-Bosker

Ufermann

Oldenburg

et al. 2019

Med Microbiol Immunol

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Human retinal pigment epithelial (hRPE) cells form a selectively permeable monolayer between the neural retina and the highly permeable choroidal vessels. Thus, hRPE cells bear important regulatory functions and are potential targets of pathogens in vivo. Endogenous bacterial endophthalmitis (EBE) is frequently caused by infections with the Gram-positive bacterium Staphylococcus aureus (S. aureus). Upon microbial infection, interferon gamma (IFN-γ), a major cytokine of the adaptive immune response, induces a broad spectrum of effector molecules, such as the tryptophan-degrading enzyme indoleamine 2,3-dioxygenase-1 (IDO1). We stimulated human RPE (hRPE) cells in vitro with proinflammatory cytokines and analyzed the expression levels and enzymatic activities of IDO1 and inducible nitric oxide synthase (iNOS), another antimicrobial effector molecule. The antimicrobial capacity was analyzed in infection experiments using S. aureus and Toxoplasma gondii (T. gondii). Our aim was to characterize the particular importance of IDO1 and iNOS during EBE. We found that an IFN-γ stimulation of hPRE cells induced the expression of IDO1, which inhibited the growth of T. gondii and S. aureus. A co-stimulation with IFN-γ, interleukin-1 beta, and tumor necrosis factor alpha induced a strong expression of iNOS. The iNOS-derived nitric oxide production was dependent on cell-culture conditions; however, it could not cause antimicrobial effects. iNOS did not act synergistically with IDO1. Instead, iNOS activity inhibited IDO1-mediated tryptophan degradation and bacteriostasis. This effect was reversible by the addition of the iNOS inhibitor NG-monomethyl-l-arginine. In conclusion, iNOS mediates anti-inflammatory effects in hRPE cells stimulated with high amounts of IFN-γ together with tumor necrosis factor alpha and Interleukin-1 beta and prevents potential IDO1-dependent tissue damage.Electronic supplementary materialThe online version of this article (10.1007/s00430-019-00627-4) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Interplay between IDO1 and iNOS in human retinal pigment epithelial cells

Spekker-Bosker

Ufermann

Oldenburg

et al. 2019

Med Microbiol Immunol

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“…Increased KTR has also been reported in cancer [28], autoimmune disease, including rheumatoid arthritis (RA) [29], and systemic lupus erythematosis (SLE) [30]. Infectious diseases are also linked to an elevated KTR [31] with a ratio that directly reflects severity [32,33]. This includes SARS CoV2 [34].…”

Section: Altered Tryptophan Metabolism (Atm) and Ktrmentioning

confidence: 99%

Staunch the Age Related Decline into Dementia, Cancer, Autoimmunity (POTS), Obesity, and Other Diseases with a Prebiotic, Probiotic, Postbiotic Triple Play

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2024

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“All diseases originate in the gut.” Hippocrates (400 BC) A healthy gut microbiome via the gut-brain-axis (GBA) elevates heart rate variability (HRV), a general measure of health and well-being. A dysbiotic gut microbiome, low in biodiversity and butyrate producers, alters tryptophan metabolism with release of proinflammatory cytokines, predominantly TNF-α, IL-6, and IL-1β. These also characterize chronic inflammation, oxidative stress, and a multitude of diseases, all exhibiting low HRV. Gut dysbiosis upregulates IFN-γ and with it IDO (indoleamine 2,3 dioxygenase). Tryptophan pivots from serotonin synthesis to that of IDO induced kynurenine, increasing the kynurenine to tryptophan ratio (KTR). An elevated KTR is positively linked to neurodegenerative and autoimmune diseases and negatively linked to HRV. Elevated IDO activity is not only enzymatic but also an intracellular signal transducer potentiated by TGF-β. This cytokine is the primary determinant of the TME. Also proposed is the gut-lung dysbiosis concept and consequent degradation of ACE2 (richest in lungs and gut). Leaky gut induced autoantibodies related to G-protein coupled receptors (GPCRs) in combination with increased Ang II further potentiate oxidative stress. Aldosterone and paroxysmal orthostatic tachycardia syndrome (POTS) paradoxes are highlighted in the context of GPCR and gut dysbiosis, and the role of Candida is explored. The triple play of a prebiotic (d-mannose), probiotic (bifidobacteria and lactobacilli), and postbiotic (butyrate) might improve intestinal barrier integrity, oppose entry of GPCR antigens, suppress the inflammatory cytokine triad, balance IFN-γ and TGF-β, suppress oxidative stress, depress KTR, elevate HRV, and extend lifespan and its quality.

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“…Increased KTR has also been reported in cancer [28], autoimmune disease, including RA [29], and SLE [30]. Infectious diseases are also linked to an elevated KTR [31] with a ratio that reflects severity [32,33]. This includes SARS CoV2 [34].…”

Section: Altered Tryptophan Metabolism (Atm) and Ktrmentioning

confidence: 99%

Staunch the Age Related Decline into Depression, Dementia, Diabetes, Obesity, Cancer, Long Covid, and Other Diseases with a Prebiotic, Probiotic, Postbiotic Triple Play

Chambers

2024

Preprint

View full text Add to dashboard Cite

“All diseases originate in the gut.” Hippocrates (400 BC) A healthy gut microbiome via the gut-brain-axis (GBA) elevates heart rate variability (HRV), a general measure of health and well-being. A dysbiotic gut microbiome, low in biodiversity and butyrate producers, triggers altered tryptophan metabolism and release of proinflammatory cytokines, predominantly TNF-α, IL-6, and IL-1β, that also characterize chronic inflammation, oxidative stress, and a multitude of diseases, all exhibiting low HRV. Gut dysbiosis upregulates IFN-γ and with it IDO (indoleamine 2,3 dioxygenase). Tryptophan pivots from serotonin synthesis to that of kynurenine, increasing the kynurenine to tryptophan ratio (KTR). An elevated KTR is positively linked to neurodegenerative and autoimmune diseases and negatively linked to HRV. Elevated IDO activity is not only enzymatic but also an intracellular signal transducer potentiated by TGF-β. This cytokine is the primary determinant of the TME. The triple play of a prebiotic (d-mannose), probiotic (bifidobacteria and lactobacilli), and postbiotic (butyrate) might improve intestinal barrier integrity, suppress the inflammatory cytokine triad, balance IFN-γ and TGF-β, depress KTR, elevate HRV, and extend lifespan.

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Role of Kynurenine Pathway in Infections

Cited by 10 publications

References 44 publications

Interplay between IDO1 and iNOS in human retinal pigment epithelial cells

Interplay between IDO1 and iNOS in human retinal pigment epithelial cells

Staunch the Age Related Decline into Dementia, Cancer, Autoimmunity (POTS), Obesity, and Other Diseases with a Prebiotic, Probiotic, Postbiotic Triple Play

Staunch the Age Related Decline into Depression, Dementia, Diabetes, Obesity, Cancer, Long Covid, and Other Diseases with a Prebiotic, Probiotic, Postbiotic Triple Play

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