scholarly journals 4-Chloro-3-hydroxyanthranilate, 6-chlorotryptophan and norharmane attenuate quinolinic acid formation by interferon-γ-stimulated monocytes (THP-1 cells)

1993 ◽  
Vol 291 (1) ◽  
pp. 11-14 ◽  
Author(s):  
K Saito ◽  
C Y Chen ◽  
M Masana ◽  
J S Crowley ◽  
S P Markey ◽  
...  
Keyword(s):  
Interferon Gamma ◽  
Quinolinic Acid ◽  
Immune Activation ◽  
Mononuclear Cells ◽  
Kynurenine Pathway ◽  
Liver Cells ◽  
Acid Formation ◽  
Peripheral Blood Mononuclear ◽  
Indoleamine 2,3 Dioxygenase ◽  
Ic50 Values

Accumulation of quinolinic acid and L-kynurenine occurs in the brain and/or blood following immune activation, and may derive from L-tryptophan following induction of indoleamine 2,3-dioxygenase and other kynurenine-pathway enzymes. In the present study a survey of various cell lines derived from either brain or systemic tissues showed that, while all cells examined responded to interferon-gamma by increased conversion of L-[13C6]tryptophan into L-kynurenine (human: B-lymphocytes, neuroblastoma, glioblastoma, lung, liver, kidney; rat brain: microglia, astrocytes and oligodendrocytes), only macrophage-derived cells (peripheral-blood mononuclear cells; THP-1, U-937) and certain liver cells (SKHep1) synthesized [13C6]quinolinic acid. Tumour necrosis factor-alpha enhanced the effects of interferon-gamma in THP-1 cells. Norharmane, 6-chloro-DL-tryptophan and 4-chloro-3-hydroxyanthranilate attenuated quinolinic acid formation by THP-1 cells with IC50 values of 51 microM, 58 microM and 0.11 microM respectively. Norharmane and 6-chloro-DL-tryptophan attenuated L-kynurenine formation with IC50 values of 43 microM and 51 microM respectively, whereas 4-chloro-3-hydroxyanthranilate had no effect on L-kynurenine accumulation. The reductions in L-kynurenine and quinolinic acid formation are consistent with the reports that norharmane is an inhibitor of indoleamine 2,3-dioxygenase, 6-chloro-DL-tryptophan is metabolized through the kynurenine pathway, and 4-chloro-3-hydroxyanthranilate is an inhibitor of 3-hydroxyanthranilate 3,4-dioxygenase. These results suggest that many tissues may contribute to the production of L-kynurenine following indoleamine 2,3-dioxygenase induction and immune activation. Quinolinic acid may be directly synthesized from L-tryptophan in both macrophages and certain types of liver cells, although uptake of quinolinic acid precursors from blood may contribute to quinolinic acid synthesis in cells that cannot convert L-kynurenine into quinolinic acid.

scholarly journals Interleukin-4 inhibits indoleamine 2,3-dioxygenase expression in human monocytes

Blood ◽  
1994 ◽  
Vol 83 (5) ◽  
pp. 1408-1411 ◽  
Author(s):  
T Musso ◽  
GL Gusella ◽  
A Brooks ◽  
DL Longo ◽  
L Varesio
Keyword(s):  
Interferon Gamma ◽  
Mononuclear Cells ◽  
Inhibitory Effect ◽  
Interleukin 4 ◽  
Human Monocytes ◽  
Peripheral Blood Mononuclear ◽  
Ifn Gamma ◽  
Indoleamine 2,3 Dioxygenase ◽  
Blood Mononuclear Cells ◽  
Negative Signal

Abstract Indoleamine 2,3-dioxygenase (IDO), a flavin-dependent enzyme that catalyzes the conversion of tryptophan to kynurenine, is induced in peripheral blood mononuclear cells by interferon-gamma (IFN gamma). Interleukin-4 (IL-4) is a cytokine that modulates the functional properties of monocytes/macrophages, and we investigated the effects of IL-4 on IDO. We showed that IL-4 inhibited the induction of IDO mRNA and IDO activity by IFN gamma in human monocytes. The inhibitory effect was evident with as little as 2 U/mL of IL-4. These results provide the first evidence that a cytokine can provide a negative signal for IDO expression and that IL-4 can influence the catabolism of tryptophan.

scholarly journals Interleukin-4 inhibits indoleamine 2,3-dioxygenase expression in human monocytes

Blood ◽  
1994 ◽  
Vol 83 (5) ◽  
pp. 1408-1411
Author(s):  
T Musso ◽  
GL Gusella ◽  
A Brooks ◽  
DL Longo ◽  
L Varesio
Keyword(s):  
Interferon Gamma ◽  
Mononuclear Cells ◽  
Inhibitory Effect ◽  
Interleukin 4 ◽  
Human Monocytes ◽  
Peripheral Blood Mononuclear ◽  
Ifn Gamma ◽  
Indoleamine 2,3 Dioxygenase ◽  
Blood Mononuclear Cells ◽  
Negative Signal

Indoleamine 2,3-dioxygenase (IDO), a flavin-dependent enzyme that catalyzes the conversion of tryptophan to kynurenine, is induced in peripheral blood mononuclear cells by interferon-gamma (IFN gamma). Interleukin-4 (IL-4) is a cytokine that modulates the functional properties of monocytes/macrophages, and we investigated the effects of IL-4 on IDO. We showed that IL-4 inhibited the induction of IDO mRNA and IDO activity by IFN gamma in human monocytes. The inhibitory effect was evident with as little as 2 U/mL of IL-4. These results provide the first evidence that a cytokine can provide a negative signal for IDO expression and that IL-4 can influence the catabolism of tryptophan.

scholarly journals Positive allosteric modulation of indoleamine 2,3-dioxygenase 1 restrains neuroinflammation

2020 ◽  
Vol 117 (7) ◽  
pp. 3848-3857 ◽  
Author(s):  
Giada Mondanelli ◽  
Alice Coletti ◽  
Francesco Antonio Greco ◽  
Maria Teresa Pallotta ◽  
Ciriana Orabona ◽  
...  
Keyword(s):  
Mode Of Action ◽  
Mononuclear Cells ◽  
Significant Proportion ◽  
Kynurenine Pathway ◽  
Neuroprotective Effects ◽  
Peripheral Blood Mononuclear ◽  
Indoleamine 2,3 Dioxygenase ◽  
Aryl Hydrocarbon

l-tryptophan (Trp), an essential amino acid for mammals, is the precursor of a wide array of immunomodulatory metabolites produced by the kynurenine and serotonin pathways. The kynurenine pathway is a paramount source of several immunoregulatory metabolites, including l-kynurenine (Kyn), the main product of indoleamine 2,3-dioxygenase 1 (IDO1) that catalyzes the rate-limiting step of the pathway. In the serotonin pathway, the metabolite N-acetylserotonin (NAS) has been shown to possess antioxidant, antiinflammatory, and neuroprotective properties in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). However, little is known about the exact mode of action of the serotonin metabolite and the possible interplay between the 2 Trp metabolic pathways. Prompted by the discovery that NAS neuroprotective effects in EAE are abrogated in mice lacking IDO1 expression, we investigated the NAS mode of action in neuroinflammation. We found that NAS directly binds IDO1 and acts as a positive allosteric modulator (PAM) of the IDO1 enzyme in vitro and in vivo. As a result, increased Kyn will activate the ligand-activated transcription factor aryl hydrocarbon receptor and, consequently, antiinflammatory and immunoregulatory effects. Because NAS also increased IDO1 activity in peripheral blood mononuclear cells of a significant proportion of MS patients, our data may set the basis for the development of IDO1 PAMs as first-in-class drugs in autoimmune/neuroinflammatory diseases.

scholarly journals Vitamin D treatment of peripheral blood mononuclear cells modulated immune activation and reduced susceptibility to HIV-1 infection of CD4+ T lymphocytes

PLoS ONE ◽  
2019 ◽  
Vol 14 (9) ◽  
pp. e0222878 ◽  
Author(s):  
Sandra M. Gonzalez ◽  
Wbeimar Aguilar-Jimenez ◽  
Edison Trujillo-Gil ◽  
Wildeman Zapata ◽  
Ruey-Chyi Su ◽  
...  
Keyword(s):  
Vitamin D ◽  
T Lymphocytes ◽  
Peripheral Blood Mononuclear Cells ◽  
Immune Activation ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells ◽  
Hiv 1

scholarly journals Dose and duration of interferon γ pre-licensing interact with donor characteristics to influence the expression and function of indoleamine-2,3-dioxygenase in mesenchymal stromal cells

2020 ◽  
Vol 17 (167) ◽  
pp. 20190815
Author(s):  
Devlin T. Boyt ◽  
Lauren K. Boland ◽  
Anthony J. Burand ◽  
Alex J. Brown ◽  
James A. Ankrum
Keyword(s):  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Mononuclear Cells ◽  
Inflammatory Diseases ◽  
Interferon Γ ◽  
Relative Role ◽  
Peripheral Blood Mononuclear ◽  
High Performing ◽  
Indoleamine 2,3 Dioxygenase

Human mesenchymal stromal cells (MSCs) are a leading cell therapy candidate for the treatment of immune and inflammatory diseases due to their potent regulation of immune cells. MSC expression of indoleamine-2,3-dioxygenase (IDO) upon interferon γ (IFNγ) exposure has been proposed as both a sentinel marker and key mediator of MSC immunomodulatory potency. Rather than wait for in vivo exposure to cytokines, MSCs can be pre-licensed during manufacturing to enhance IDO expression. In this study, we systematically examine the relative role that the dose of IFNγ, the duration of pre-licensing and the donor of origin play in dictating MSC production of functional IDO. We find that across three human MSC donors, MSCs increase their expression of IDO in response to both increased dose of IFNγ and duration of pre-licensing. However, with extended pre-licensing, the expression of IDO no longer predicts MSCs ability to suppress activated peripheral blood mononuclear cells. In addition, pre-licensing dose and duration are revealed to be minor modifiers of MSCs inherent potency, and thus cannot be manipulated to boost poor donors to the levels of high-performing donors. Thus, the dose and duration of pre-licensing should be tailored to optimize performance of specific donors and an emphasis on donor selection is needed to realize significant benefits of pre-licensing.

Neopterin suppresses the activity of tryptophan-degrading enzyme indoleamine 2,3-dioxygenase in human peripheral blood mononuclear cells

Pteridines ◽  
2013 ◽  
Vol 24 (3) ◽  
pp. 237-243
Author(s):  
Sebastian Schroecksnadel ◽  
Elena-Sophia Ledjeff ◽  
Johanna Gostner ◽  
Christiana Winkler ◽  
Katharina Kurz ◽  
...  
Keyword(s):  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Peripheral Blood Mononuclear ◽  
Indoleamine 2,3 Dioxygenase ◽  
Blood Mononuclear Cells ◽  
Ifn Γ

AbstractIn vitro, large amounts of neopterin are released from human monocyte-derived macrophages and dendritic cells primarily upon stimulation with Th1-type cytokine interferon-γ (IFN-γ). IFN-γ also induces the enzyme indoleamine 2,3-dioxygenase (IDO), which degrades tryptophan (TRP) to form kynurenine (KYN). IDO-mediated TRP catabolism is very effective in suppressing the proliferation of T lymphocytes as well as of pathogens in vitro and in vivo. In this study, we investigated whether exogenously added neopterin may influence IDO activity in resting and in stimulated peripheral blood mononuclear cells (PBMC). PBMC were isolated from healthy donors, and neopterin was added in a concentration range from 0.01 to 50 μmol/L. After 30 min, PBMC were stimulated or not with 10 μg/mL of mitogen phytohemagglutinin (PHA). After 48 h, culture supernatants were collected, KYN and TRP concentrations were measured by high-performance liquid chromatography, and the ratio of KYN vs. TRP was calculated as an estimate of IDO activity. Spontaneous as well as PHA-induced TRP breakdown was suppressed by exogenously added neopterin in a dose-dependent way; the lowest active concentration of neopterin was <100 nmol/L. As neopterin concentrations in the nanomolar range are commonly observed in patients suffering from infections, sepsis, or uremia, our results suggest that neopterin formation might also serve as a feedback mechanism to slow down TRP degradation in vivo.

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