Immuno-Regulatory Function of Indoleamine 2,3 Dioxygenase through Modulation of Innate Immune Responses

Poormasjedi‐Meibod, Malihe‐Sadat; Jalili, Raza B.; Hosseini‐Tabatabaei, Azadeh; Hartwell, Ryan; Ghahary, Aziz

doi:10.1371/journal.pone.0071044

Cited by 31 publications

(31 citation statements)

References 45 publications

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“…However, under a similar experimental condition, the number of macrophages was not significantly changed between treated and untreated wounds. This finding is consistent with our previous report indicating that Kyn has no influence on proliferation of macrophages in an in vivo model …”

Section: Discussionsupporting

confidence: 94%

Effects of kynurenine on CD3+ and macrophages in wound healing

Elizei

Poormasjedi‐Meibod

et al. 2015

Wound Repair Regeneration

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As prolongation of the inflammation phase in a healing process frequently leads to wound impairment, here we queried whether kynurenine (Kyn) could modulate this phase of wound healing. To address this, a protein microarray, quantitative polymerase chain reaction (qPCR), flow cytometry for immune cells and immune cell proliferation in the presence and absence of Kyn were conducted and compared. The result of a protein microarray revealed that the expression of 12 pro-inflammatory cytokines and chemokines was modulated in Kyn-treated mouse splenocytes as compared with those of control. These findings were then evaluated by conducting a qPCR for the gene expression of these factors and showed a significant reduction in the gene expression of majority of these cytokines and chemokines (interleukin [IL]-2, IL-17, C-X-C motif chemokine ligand [CXCL] 10, CXCL1, C-C motif ligand [CCL] 12, CXCL9, CCL4, CXCL2, and CCL5) in response to Kyn treatment. To test the anti-inflammatory effect of Kyn in an animal model, dorsal surface wounds were generated in a mouse model and wounds received daily topical application of either nothing (control), dermal cream (second control), or Kyn cream using uninjured skin tissue as another control. The wounded tissues were harvested on days 3, 6, and 10 postwounding. As anticipated, the results of fluorescence-activated cell sorting analysis revealed that upon wounding, the number of total infiltrated CD3+ cells and macrophages (CD11b+) significantly increased on day 3, peaked on day 6, and reduced on day 10 post-wounding. Interestingly, as compared with those of uninjured and dermal cream alone-treated wounds, Kyn treatment significantly reduced the number of infiltrated CD3+ cells, but not CD11b+ cells, at different time intervals examined. These findings collectively suggest that Kyn, as a small molecule, can potentially be used to overcome the difficulties associated with persistency of inflammation in healing wounds.

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Section: Discussionsupporting

confidence: 94%

Effects of kynurenine on CD3+ and macrophages in wound healing

Elizei

Poormasjedi‐Meibod

et al. 2015

Wound Repair Regeneration

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“…NO is an important macrophage immune effector molecule that is involved in immune regulation and the defense response, and its production is regulated by iNOS (23). When stimulated, Raw264.7 cells produce abundant quantities of NO, which assists macrophages in the immune response against pathogens (20). The results of the present study demonstrate that SAP-1 increased the levels of iNOS gene expression in RAW264.7 cells, and increased the production of NO by RAW264.7 cells.…”

Section: Discussionsupporting

confidence: 57%

“…The sample was centrifuged at 5,000 x g (-4˚C) for 10 min, and the supernatant discarded. The residue was washed with 75% ethanol, and the total RNA was eluted with diethyl pyrocarbonate water (18)(19)(20)(21). The purity of RNA was determined from the A260/A280 ratio using ultraviolet spectrophotometry (Nanodrop ND1000; Thermo Fisher Scientific, Inc.).…”

Section: Reverse Transcription-quantitative Polymerase Chain Reactionmentioning

confidence: 99%

Saccharum Alhagi polysaccharide-1 and -2 promote the immunocompetence of RAW264.7 macrophages inï¿½vitro

Xiang

Zhao

et al. 2018

Exp Ther Med

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Abstract. The in vitro immune activities of Saccharum Alhagi polysaccharides (SAP) have been previously studied. The present study aimed to investigate the effects of SAP-1 and SAP-2 on the activity of RAW264.7 mouse macrophages. RAW264.7 cells were treated with 150, 300 and 600 mg/l concentrations of SAP-1 (a 50% alcohol precipitation) and SAP-2 (an 80% alcohol precipitation) or with 10 mg/l lipopolysaccharide. Untreated cells were used as a negative control. An MTT assay was used to detect the proliferation of the cells, and Hoechst 33528 staining was conducted in order to visualize the cell nuclei. Additionally, the Griess method was used to measure nitric oxide (NO) levels. A neutral red uptake assay was performed to determine the phagocytic activity of the macrophages, and ELISAs were performed to detect cytokine levels. Furthermore, reverse transcription-quantitative polymerase chain reaction was used to measure the mRNA expression of certain cytokines. The results demonstrated that SAP increased the proliferative activity and activated the immune function of RAW264.7 cells, and was lacking in cytotoxicity. In addition, SAP-1 exhibited a stronger effect in promoting RAW264.7 cell proliferation than did SAP-2. Furthermore, SAP-1 and SAP-2 significantly increased the level of NO, with the effect of SAP-1 being stronger than that of SAP-2. SAP-1 increased the phagocytic activity of RAW264.7 cells and promoted the secretion of the cytokines interleukin (IL)-1β, IL-2 and tumor necrosis factor (TNF)-α by RAW264.7 cells, with an effect that was stronger than that of SAP-2. Finally, different concentrations of SAP-1 or SAP-2 had distinct effects in upregulating the expression of TNF-α, IL-1β, nuclear factor-κB and inducible nitric oxide synthase mRNA. The results of the present study demonstrate that SAP is capable of enhancing the immune activity of mouse macrophages.

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“…For example, IDO1 expression has been identified as a determinant of macrophage M1 rather than M2 phenotype, with the enzyme signalling in favour of the anti-inflammatory M2 phenotype [255,256]. Studies in the RAW264.7 murine macrophage cell line indicated that incubation of these cells with IDO1-expressing fibroblasts resulted in reduced NOS2 expression and macrophage viability due to L-Trp deprivation [257]. IDO1-expressing fibroblasts similarly reduced macrophage numbers and xenograft survival in a macrophage-dependent pancreatic islet xenograft-rejection model [257].…”

Section: Lymphocytesmentioning

confidence: 99%

“…Studies in the RAW264.7 murine macrophage cell line indicated that incubation of these cells with IDO1-expressing fibroblasts resulted in reduced NOS2 expression and macrophage viability due to L-Trp deprivation [257]. IDO1-expressing fibroblasts similarly reduced macrophage numbers and xenograft survival in a macrophage-dependent pancreatic islet xenograft-rejection model [257]. Further evidence for control of macrophages by IDO1-expressing bystander cells comes from a report with IDO1-expressing endometrial stromal cells impairing macrophage phagocytic activity in a manner dependent on IL-33 production [258].…”

Section: Lymphocytesmentioning

confidence: 99%

Role of indoleamine 2,3-dioxygenase in health and disease

et al. 2015

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IDO1 (indoleamine 2,3-dioxygenase 1) is a member of a unique class of mammalian haem dioxygenases that catalyse the oxidative catabolism of the least-abundant essential amino acid, L-Trp (L-tryptophan), along the kynurenine pathway. Significant increases in knowledge have been recently gained with respect to understanding the fundamental biochemistry of IDO1 including its catalytic reaction mechanism, the scope of enzyme reactions it catalyses, the biochemical mechanisms controlling IDO1 expression and enzyme activity, and the discovery of enzyme inhibitors. Major advances in understanding the roles of IDO1 in physiology and disease have also been realised. IDO1 is recognised as a prominent immune regulatory enzyme capable of modulating immune cell activation status and phenotype via several molecular mechanisms including enzyme-dependent deprivation of L-Trp and its conversion into the aryl hydrocarbon receptor ligand kynurenine and other bioactive kynurenine pathway metabolites, or non-enzymatic cell signalling actions involving tyrosine phosphorylation of IDO1. Through these different modes of biochemical signalling, IDO1 regulates certain physiological functions (e.g. pregnancy) and modulates the pathogenesis and severity of diverse conditions including chronic inflammation, infectious disease, allergic and autoimmune disorders, transplantation, neuropathology and cancer. In the present review, we detail the current understanding of IDO1's catalytic actions and the biochemical mechanisms regulating IDO1 expression and activity. We also discuss the biological functions of IDO1 with a focus on the enzyme's immune-modulatory function, its medical implications in diverse pathological settings and its utility as a therapeutic target.

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Immuno-Regulatory Function of Indoleamine 2,3 Dioxygenase through Modulation of Innate Immune Responses

Cited by 31 publications

References 45 publications

Effects of kynurenine on CD3+ and macrophages in wound healing

Effects of kynurenine on CD3+ and macrophages in wound healing

Saccharum Alhagi polysaccharide-1 and -2 promote the immunocompetence of RAW264.7 macrophages inï¿½vitro

Role of indoleamine 2,3-dioxygenase in health and disease

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