Immunocytochemical localization of the endogenous neuroexcitotoxin quinolinate in human peripheral blood monocytes/macrophages and the effect of human T-cell lymphotropic virus type I infection.

Venkateshan, C. N.; Narayanan, Rekha; Espey, Michael Graham; Moffett, John R.; Gajdusek, D. Carleton; Gibbs, Clarence J.; Namboodiri, M. A. A.

doi:10.1073/pnas.93.4.1636

Cited by 16 publications

(8 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…8). In support of this model, we and colleagues have shown that macrophages and microglia can metabolize KYN to QUIN (Venkateshan et al . 1996; Heyes et al .…”

Section: Discussionmentioning

confidence: 53%

Kynurenine pathway metabolism in human astrocytes: a paradox for neuronal protection

Guillemin

Kerr

Smythe

et al. 2001

Journal of Neurochemistry

473

460

View full text Add to dashboard Cite

There is good evidence that the kynurenine pathway (KP) and one of its products, quinolinic acid (QUIN), play a role in the pathogenesis of neurological diseases, in particular AIDS dementia complex. Although QUIN has been shown to be produced in neurotoxic concentrations by macrophages and microglia, the role of astrocytes in QUIN production is controversial. Using cytokine-stimulated cultures of human astrocytes, we assayed key enzymes and products of the KP. We found that human astrocytes lack kynurenine hydroxylase so that large amounts of kynurenine and the QUIN antagonist kynurenic acid were produced. However, the amounts of QUIN that were synthesized were subsequently completely degraded. We then showed that kynurenine in concentrations comparable with those produced by astrocytes led to signi®cant production of QUIN by macrophages. These results suggest that astrocytes alone are neuroprotective by minimizing QUIN production and maximizing synthesis of kynurenic acid. However, it is likely that, in the presence of macrophages and/or microglia, astrocytes become indirectly neurotoxic by the production of large concentrations of kynurenine that can be secondarily metabolized by neighbouring or in®ltrating monocytic cells to form the neurotoxin QUIN.

show abstract

“…8). In support of this model, we and colleagues have shown that macrophages and microglia can metabolize KYN to QUIN (Venkateshan et al . 1996; Heyes et al .…”

Section: Discussionmentioning

confidence: 53%

Kynurenine pathway metabolism in human astrocytes: a paradox for neuronal protection

Guillemin

Kerr

Smythe

et al. 2001

Journal of Neurochemistry

473

460

View full text Add to dashboard Cite

show abstract

“…Based upon previous immunohistochemical studies that have demonstrated that strong staining for quinolinate is limited to cells of the immune system, we have postulated that quinolinate serves an immune-system-specific function (Moffett et al 1994a(Moffett et al ,b, 1997Espey et al 1995Espey et al , 1996Venkateshan et al 1996;Namboodiri et al 1996). The present study has been designed to assess the effect of increased extracellular tryptophan and kynurenine on quinolinate staining in several organs known to contain varying amounts of quinolinate (Saito et al 1993b).…”

Section: Discussionmentioning

confidence: 92%

Differential effects of kynurenine and tryptophan treatment on quinolinate immunoreactivity in rat lymphoid and non-lymphoid organs

et al. 1998

View full text Add to dashboard Cite

Quinolinate is a tryptophan metabolite and an intermediary in nicotinamide adenine dinucleotide (NAD+) synthesis in hepatocytes. Kynurenine is an upstream metabolite in the same biochemical pathway. Under normal physiological conditions, kynurenine is thought to be produced primarily in the liver as an NAD+ precursor. However, during immune stimulation or inflammation, numerous extrahepatic tissues convert systemic tryptophan to kynurenine, and its concentration subsequently rises dramatically in blood. The fate and role of extrahepatic kynurenine are uncertain. In order to begin addressing this question, the present study was performed to determine which cell types can produce quinolinate from either systemic tryptophan or kynurenine. By using highly specific antibodies to protein-coupled quinolinate, we found that intraperitoneal injections of tryptophan led to increased quinolinate immunoreactivity primarily in hepatocytes, with moderate increases in tissue macrophages and splenic follicles. In contrast, intraperitoneal injections of kynurenine did not result in any significant increase in hepatocyte quinolinate immunoreactivity, but rather led to dramatic increases in immunoreactivity in tissue macrophages, splenic white pulp, and thymic medulla. These findings suggest that hepatocytes do not make significant use of extracellular kynurenine for quinolinate or NAD+ synthesis, and that, instead, extrahepatic kynurenine is preferentially metabolized by immune cells throughout the body. The possible significance of the preferential metabolism of kynurenine by immune cells during an immune response is discussed.

show abstract

“… 50 , 51 , 52 In the liver, it is well documented that hepatocytes produce quinolinate transiently in the course of NAD + synthesis, 49 but quinolinate does not accumulate in the liver under normal conditions 53 . Monocytes have been found to be robust producers of quinolinate when stimulated with IFN‐γ and other immune stimulants 54 , 55 , 56 . In fact, the spleen has one of the highest levels of quinolinate in any tissue or organ 42…”

Section: Quinolinate and The Immune Systemmentioning

confidence: 99%

Tryptophan and the immune response

2003

View full text Add to dashboard Cite

SummaryThe immune system continuously modulates the balance between responsiveness to pathogens and tolerance to non-harmful antigens. The mechanisms that mediate tolerance are not well understood, but recent findings have implicated tryptophan catabolism through the kynurenine metabolic pathway as one of many mechanisms involved. The enzymes that break down tryptophan through this pathway are found in numerous cell types, including cells of the immune system. Some of these enzymes are induced by immune activation, including the rate limiting enzyme present in macrophages and dendritic cells, indoleamine 2,3-dioxygenase (IDO). It has recently been found that inhibition of IDO can result in the rejection of allogenic fetuses, suggesting that tryptophan breakdown is necessary for maintaining aspects of immune tolerance. Two theories have been proposed to explain how tryptophan catabolism facilitates tolerance. One theory posits that tryptophan breakdown suppresses T cell proliferation by dramatically reducing the supply of this critical amino acid. The other theory postulates that the downstream metabolites of tryptophan catabolism act to suppress certain immune cells, probably by pro-apoptotic mechanisms. Reconciling these disparate views is crucial to understanding immune-related tryptophan catabolism and the roles it plays in immune tolerance. In this review we examine the issue in detail, and offer additional insight provided by studies with antibodies to quinolinate, a tryptophan catabolite which is also necessary for nicotinamide adenine dinucleotide (NAD +) production. In addition to the immunomodulatory actions of tryptophan catabolites, we discuss the possible involvement of quinolinate as a means of replenishing NAD + in leucocytes, which is depleted by oxidative stress during an immune response.

show abstract

Immunocytochemical localization of the endogenous neuroexcitotoxin quinolinate in human peripheral blood monocytes/macrophages and the effect of human T-cell lymphotropic virus type I infection.

Cited by 16 publications

References 38 publications

Kynurenine pathway metabolism in human astrocytes: a paradox for neuronal protection

Kynurenine pathway metabolism in human astrocytes: a paradox for neuronal protection

Differential effects of kynurenine and tryptophan treatment on quinolinate immunoreactivity in rat lymphoid and non-lymphoid organs

Tryptophan and the immune response

Contact Info

Product

Resources

About