Interferon-lnduced Indoleamine 2,3-Dioxygenase Activity in Human Mononuclear Phagocytes

Carlin, Joseph M.; Borden, Ernest C.; Sondel, Paul M.; Byrne, Gerald I.

doi:10.1002/jlb.45.1.29

Cited by 216 publications

(185 citation statements)

References 20 publications

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“…In macrophages and human placental cells in culture, IDO expression is regulated by IFN-␥ (27,28). We have previously shown that both IFN-␥ and TNF-␣ are up-regulated in the placenta following L. monocytogenes infection (17).…”

Section: Ifn-␥ But Not Csf-1 Nor Tnf-␣ Regulates Ido Expression In Thmentioning

confidence: 99%

Indoleamine 2,3-Dioxygenase Is Regulated by IFN-γ in the Mouse Placenta DuringListeria monocytogenesInfection

Mackler¹,

Barber²,

Takikawa

et al. 2003

The Journal of Immunology

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The tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase (IDO) is expressed in macrophages that have been differentiated in the presence of CSF-1 and is important in the containment of intracellular pathogens. IDO also appears to play a role in suppression of T cell responses in a variety of contexts. In the placenta, its enzymatic activity is believed to establish a chemical barrier that protects the fetal allograft from T cell-mediated immune aggression. We have studied the regulation of IDO in the utero-placental unit of mice following infection with the Gram-positive, intracellular bacterium Listeria monocytogenes that has a predilection for replication in the decidua basalis. IDO mRNA and protein expression is enhanced in the utero-placental unit following infection with L. monocytogenes. However, in contrast to the human where IDO is expressed by the CSF-1R-positive syncytial trophoblast, IDO is not expressed in murine trophoblastic tissue but instead is found in stromal cells of the decidua basalis and metrial gland and following infection, in endothelial cells. Using mice carrying null mutations in cytokine/growth factor genes, we explored the regulation of IDO in the placenta. Consistent with the absence of CSF-1R expression in the IDO-expressing cells of mice, neither the basal levels of IDO nor its induction following infection is affected by the absence of CSF-1. However, although the basal level of IDO is normal, the enhanced expression during Listeriosis is completely abrogated in the absence of IFN-γ, a cytokine required for the resolution of this infection. These data suggest that IDO plays a role in resolving bacterial infection in the placenta while at the same time maintaining a barrier to T cells whose presence might result in fetal rejection.

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Section: Ifn-␥ But Not Csf-1 Nor Tnf-␣ Regulates Ido Expression In Thmentioning

confidence: 99%

Indoleamine 2,3-Dioxygenase Is Regulated by IFN-γ in the Mouse Placenta DuringListeria monocytogenesInfection

Mackler¹,

Barber²,

Takikawa

et al. 2003

The Journal of Immunology

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“…While in most investigated in vitro models, IFN-γ is the main inducer of IDO in macrophages, DC, fibroblasts, and microglia [2][3][4][5]46], its expression can also be triggered by lipopolysaccharide (LPS) through an IFN-γ-independent mechanism [47]. The induction of IDO expression without IFN-γ signaling is not dependent on signal transducer and activator of transcription 1α and interferon regulatory factor-1 but requires p38 mitogen-activated protein kinase and nuclear factor-κB [48].…”

Section: Possible Mechanisms Of Ido-mediated Tolerance Inductionmentioning

confidence: 99%

“…The main inducer of IDO, the proinflammatory cytokine IFN-γ, is the key cytokine of encephalitogenic Th1 cells. TNF-α is also secreted by these Th1 cells and acts synergistically with IFN-γ on the induction of IDO in macrophages and microglia [2,6].…”

Section: The Kynurenine Pathway In Eae and Msmentioning

confidence: 99%

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IDO expression in the brain: a double-edged sword

2007

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The tryptophan-catabolizing enzyme indoleamine-2,3-dioxygenase (IDO) initiates the first and ratelimiting step of the kynurenine pathway. It is induced by proinflammatory cytokines such as interferon-β and interferon-γ and has established effects in the control of intracellular parasites. The recent detection of its decisive function in immune tolerance at the maternal-fetal interface stimulated various studies unraveling its regulatory effect on T cells in many pathologies. In the brain, IDO can be induced in microglia by interferon-γ-producing T helper (Th) 1 cells, thereby initiating a negative feedback loop which downmodulates neuroinflammation in experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS). This protective effect could to be counteracted by the production of neurotoxic metabolites of the kynurenine pathway such as quinolinic acid, which are produced upon IDO induction. Some metabolites of the kynurenine pathway can pass the blood-brain barrier and thus could act as neurotoxins, e.g., during systemic infection. In this paper, we give a brief overview on established immune regulatory functions of IDO, review recent data on IDO expression in the brain, and propose that autoimmune neuroinflammation and the increasingly appreciated neuronal damage in MS are linked by Th1-mediated IDO induction through subsequent synthesis of toxic metabolites of tryptophan.

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“…It leads directly to an opening of the indole ring of tryptophan, thus forming N-formylkynurenine, which rapidly degrades to L-kynurenine [6]. The strongest known inducer is IFN-c, shown in cultured fibroblasts [7], macrophages [8], dendritic cells [9] and many cancer cell lines [10]. The IDO-induced tryptophan depletion, as well as the release of its catabolites in the extracellular environment, arrests activated T lymphocytes in the G1 phase, thereby promoting tolerance [11,12] and leading to apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Function of indoleamine 2,3‐dioxygenase in corneal allograft rejection and prolongation of allograft survival by over‐expression

et al. 2006

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Indoleamine 2,3-dioxygenase (IDO) suppresses T cell responses by its action in catabolising tryptophan. It is important in maintenance of immune privilege in the placenta. We investigated the activity of IDO in the cornea, following corneal transplantation and the effect of IDO over-expression in donor corneal endothelium on the survival of corneal allografts. IDO expression was analysed and functional activity was quantified in normal murine cornea and in corneas following transplantation as allografts. Low levels of IDO, at both mRNA and protein levels, was detected in the normal cornea, up-regulated by IFN-c and TNF. Expression of IDO in cornea was significantly increased following corneal transplantation. However, inhibition of IDO activity in vivo had no effect on graft survival. Following IDO cDNA transfer, murine corneal endothelial cells expressed functional IDO, which was effective at inhibiting allogeneic T cell proliferation. Over-expression of IDO in donor corneal allografts resulted in prolonged graft survival. While, on one hand, our data indicate that IDO may augment corneal immune privilege, up-regulated IDO activity following cytokine stimulation may serve to inhibit inflammatory cellular responses. While increasing IDO mRNA expression was found in allogeneic corneas at rejection, over-expression in donor cornea was found to significantly extend survival of allografts.

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Interferon-lnduced Indoleamine 2,3-Dioxygenase Activity in Human Mononuclear Phagocytes

Cited by 216 publications

References 20 publications

Indoleamine 2,3-Dioxygenase Is Regulated by IFN-γ in the Mouse Placenta DuringListeria monocytogenesInfection

Indoleamine 2,3-Dioxygenase Is Regulated by IFN-γ in the Mouse Placenta DuringListeria monocytogenesInfection

IDO expression in the brain: a double-edged sword

Function of indoleamine 2,3‐dioxygenase in corneal allograft rejection and prolongation of allograft survival by over‐expression

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