由 sufang 在 四, 11/20/2014 – 13:20 發表 Pre-published IDO1 KYN
Remarkable Role of Indoleamine 2,3-Dioxygenase and Tryptophan Metabolites in Infectious Diseases: Potential Role in Macrophage-Mediated Inflammatory Diseases (PubMed) (pdf 4235)
Figure 1. Schematic overview of the kynurenine pathway. It is estimated that only 1% of dietary tryptophan (TRP) can be converted into serotonin (5-HT). The remaining 99% of TRP is metabolized via the kynurenine (KYN) pathway. Tryptophan hydroxylase (TH), 5-hydroxy TRP (5-HTP), N-acetylserotonin (NAS), indoleamine 2,3-dioxygenase 1 and 2 (IDO1/2), tryptophan 2,3-dioxygenase (TDO), kynurenine 3-monooxygenase (KMO), kynurenine aminotransferase (KAT I, II, III), kynurenic acid (KA), anthranilic acid (AA), 3-hydroxykynurenine (3-HK), xanthurenic acid (XA), 3-hydroxyanthranilic acid (3-HAA), 3-hydroxyanthranilic acid oxidase (3-HAO), quinolinic acid (QUIN), quinolinic-acid phosphoribosyl transferase (QPRT), nicotinic acid mononucleotide (NaMN), nicotinamide mononucleotide adenylyltransferase (NMNAT), nicotinamide adenine dinucleotide (NAD).
Figure 2: T-cell immune regulation by IDO1. (a) IDO1 is induced by IFN-γ-dependent and/or -independent signal pathways, depending on the variety of immune stimuli by macrophages and dendritic cells (DCs) [28, 83]. IDO1 activity is suppressed by the formation of NO or the competitive enzyme inhibitor, 1MT. Marked increases in IDO1 suppress immune responses by locally depleting L-TRP and preventing T-cell proliferation [44]. Expression of IDO1 has been observed in certain types of activated macrophages and DCs. IDO1-expressing cells deplete TRP from the extracellular milieu and secrete TRP metabolites, including KYN, 3-HK, 3-HAA, and QUIN, which induce T-cell apoptosis and suppress immune responses in vitro. (b) CD19+ plasmacytoid DCs (pDCs) express high levels of IDO1, which can activate mature regulatory T (Treg) cells via activation of the protein kinase general control nonderepressing-2 (GCN2) pathway of protein synthesis inhibition [84]. pDC-produced IDO1 and activated Treg can convert naïve T cells into new Treg. IDO1 acts in an autocrine manner to suppress pDC production of IL-6, which prevents the conversion of Treg into IL-17-producing Th17 proinflammatory cells [79]. IDO1 also downregulates type I IFN (IFN-α) production by pDC [80].
Figure 3: IDO1 induction and proinflammatory cytokines. IFN-γ drives intense enzymatic IDO1 activity, resulting in TRP depletion and high-level production of immunoregulatory TRP metabolites, KYNs, which may foster Tregs expansion. Induced Tregs use TGF-β to maintain an IDO1-dependent regulatory environment, with IDO1 mostly functioning as a signaling molecule. Both mechanisms are interrupted by IL-6, which drives IDO1 degradation as potent inflammatory stimuli enter the local environment [85].
Figure 4: The mechanism of IDO1 regulation on viral infectious diseases. Innate defense occurs when pathogens contact or invade host cells and elicit the production of cytokines and chemokines, which in turn induce an influx of immune cells that affect pathogen clearance. Type I IFNs are critical mediators of innate immunity and limit disease caused by many viruses [73, 86]. The enhancement of TRP breakdown by IDO1 regulates the signal pathway for IFNs production, and TRP metabolites might contribute to the function of IFNs producing cells.