Metabolism of Pterins in the Cellular Immune System of Man and Mouse

Schoedon, Gabriele; Niederwieser, A.; Curtius, Hans−Christoph; Fontana, Adriano; Troppmair, J.; Huber, Christoph

doi:10.1515/9783111503844.161

Cited by 4 publications

(5 citation statements)

References 3 publications

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“…In macrophages the accumulated NHzTP seems to be quickly converted to dihydroneopterin which is released in the extracellular compartment. In this way GTP cyclohydrolase I is fully active in human macrophages but partially feedbackinhibited by BH4 in T-lymphocytes [27].…”

Section: Discussionmentioning

confidence: 99%

Biosynthesis and metabolism of pterins in peripheral blood mononuclear cells and leukemia lines of man and mouse

et al. 1987

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The cellular origin and the control of neopterin release associated with immune stimulation was studied in cell cultures. Using purified human mononuclear cells, the intracellular change in concentrations of GTP and pterins was measured under various kinds of stimulation. Three enzymes involved in tetrahydrobiopterin biosynthesis, i.e. GTP cyclohydrolase I, 6-pyruvoyl tetrahydropterin synthase and sepiapterin reductase, were also determined.Human macrophages stimulated with culture supernatant from activated T-lymphocytes were the main producers of neopterin. In these cells, GTP cyclohydrolase I activity was elevated due to high GTP levels and therefore neopterin accumulated. Human macrophages lack 6-pyruvoyl tetrahydropterin synthase activity. Exogenous tetrahydrobiopterin added to the culture medium of stimulated T cells and macrophages suppressed the elevation of GTP cyclohydrolase I activity and neopterin concentration, but not the elevation of intracellular GTP.Stimulation of macrophages with recombinant human interferon-y and neutralization of the effect of T cell supernatants by addition of a monoclonal antibody specific for human interferon-y showed that immune interferon induced the alterations in GTP cyclohydrolase I activity and neopterin concentration. In the human macrophage line U-937 and in the leukemia line HL-60, no GTP cyclohydrolase I activity or intracellular pterins were detected, but high levels of GTP. In mouse mononuclear cells, no neopterin was detected, but biopterin and pterin. After stimulation, biopterin was elevated in the same way as neopterin in human mononuclear cells. This is explained by the different regulation of the rate-limiting steps of tetrahydrobiopterin biosynthesis in man and in mouse. These results suggest that neopterin is an unspecific marker for the activation of the cellular immune system.

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Section: Discussionmentioning

confidence: 99%

Biosynthesis and metabolism of pterins in peripheral blood mononuclear cells and leukemia lines of man and mouse

et al. 1987

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“…3B) might be explained by down-regulation of GTP cyclohydrolase in activated macrophages. Since GTP cyclohydrolase is the only BH, biosynthetic enzymes responding with a dramatic increase in activity upon immune activation [20], and since hormonal regulation of the enzyme has been described [21], it could clearly be a target for dexamethasone. Indeed, in human macrophages, a 48-h treatment with 0.1 pM dexamethasone resulted in 50% suppression of GTP cyclohydrolase expression, as determined by ELISA using our specific monoclonal antibody [22] (G. Schoedon and M. Schneemann, unpublished observation).…”

Section: Discussionmentioning

confidence: 99%

“…Since, in man, the rate-limiting enzyme of de novo BH, biosynthesis is not GTP cyclohydrolase [20], inhibitors of later steps of the cofactor biosynthesis could be even more specific and effective for the treatment of pathologic conditions mediated by NO.…”

Section: Discussionmentioning

confidence: 99%

“…In preliminary studies of experimental endotoxin shock in mice, 2,4-diamino-6-hydroxypyrimidine could improve survival of lethally challenged animals [33]. Since, in man, the rate-limiting enzyme of de novo BH, biosynthesis is not GTP cyclohydrolase [20], inhibitors of later steps of the cofactor biosynthesis could be even more specific and effective for the treatment of pathologic conditions mediated by NO.…”

Section: Discussionmentioning

confidence: 99%

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Regulation of the L‐arginine‐dependent and tetrahydrobiopterin‐dependent biosynthesis of nitric oxide in murine macrophages

Schoedon

Schneemann

Hofer

et al. 1993

European Journal of Biochemistry

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Nitric oxide is a recently discovered biomolecule with a broad range of actions. The present study investigated the regulation of nitric oxide synthase activity by dexamethasone and the cofactor tetrahydrobiopterin in murine macrophages. The influence of the tetrahydrobiopterin biosynthesis inhibitors 2,4-diamino-6-hydroxypyrimidine, an inhibitor of GTP cyclohydrolase I, and phenprocoumon, an inhibitor of sepiapterin reductase, on the synthesis of nitric oxide was investigated. Dexamethasone decreased the nitric oxide production due to direct inhibition of the induction of nitric oxide synthase and of GTP cyclohydrolase. Substitution of tetrahydrobiopterin via sepiapterin could not overcome the dexamethasone-mediated inhibition. 2,4-Diamino-6-hydroxypyrimidine abolished nitric oxide synthesis and synergized with dexamethasone, completely eliminating nitric oxide production. Phenprocoumon inhibited~ production of nitric oxide via interference with later steps of tetrahydrobiopterin biosynthesis. An exogenous supply of tetrahydrobiopterin through sepiapterin led to a further increase of nitric oxide production, even in fully activated macrophages. The 'amount of nitric oxide produced by murine macrophages is therefore limited by the amount of tetrahydrobiopterin present in the cells. Inhibitors of tetrahydrobiopterin biosynthesis could provide a novel approach for therapy of pathological conditions mediated by nitric oxide, such as septic shock.Nitric oxide has recently been brought into focus as an effector molecule involved in non-oxidative killing of bacteria, protozoa, fungi and tumour cells by rodent macrophages [l, 21. Furthermore, NO is suggested to account for the action of endothelium-derived relaxing factor, a product of vascular endothelial cells [3], and as a signaling agent in neurons [4]. NO is synthesized by NO synthase through oxidation of either one of the two equivalent terminal guanidin0 nitrogen atoms from L-arginine, yielding L-citrulline and the active radical. The NO synthases characterized so far exist in two forms, (a) as a constitutive form, which is Ca2+/ calmodulin dependent, expressed in brain [5] and endothelial cells [6]. (b) The NO synthase expressed in activated macrophages [7] is inducible by cytokines and bacterial endotoxin. This form was previously thought to be Ca2+ independent, but was recently shown to contain calmodulin as a tightly . It is endogenously synthesized by the pathway shown in Fig. 1. The complex reaction mechanism of NO synthases, addressing the BH, requirement, has recently been partially elucidated Glucocorticoids have a substantial effect on the natural resistence against a broad range of bacteria and fungi [14]. Recently, it has been reported that dexamethasone reduces the activity of the inducible NO synthase in the murine macrophage-like tumor cell line, J774 [15].The present study investigated the influence of dexamethasone on L-arginine metabolism and biosynthesis of BH, in respect to NO production in murine peritoneal macrophages. The regulatory role o...

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“…It is now generally accepted that NP is released from monocytes/ macrophages, that interferon-7' (INF-y), one of the immunomodulators produced by activated T cells, is the only inducer for NP secretion from macrophages [2,3], and that 1NF-~ augments the intracellular concentration ofguanosine triphosphate as well as the conversion of it to NP [4]. Several biological roles of pteridines have been reported so far.…”

Section: Introductionmentioning

confidence: 99%

Neopterin as an endogenous antioxidant

Kojima¹,

Icho²,

Kajiwara³

et al. 1992

FEBS Letters

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The in vitro potency of neopterin (NP) as an antloxidant and its in vivo activity to suppress alloxan.induced diabetes were investigated. The reduced form of neopterin,5,6,7,, showed an e~trcmely high supcroxide anion radical scavenging activity in two assay s:,,stems, i,e, xanthine/xanthine oxidase-and macrophage/phorbol myristate acetate (PMA).rcaction systems. NPH-4 also inhibited the oxidation of linoleie acid about as effectively as uric acid. Furthermore, NPH-4 ~md NP effectively suppressed alloxan-induced mouse diabetes. Th~e results suggest that pteridines play an important role as endogenous antioxidants,

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Metabolism of Pterins in the Cellular Immune System of Man and Mouse

Cited by 4 publications

References 3 publications

Biosynthesis and metabolism of pterins in peripheral blood mononuclear cells and leukemia lines of man and mouse

Biosynthesis and metabolism of pterins in peripheral blood mononuclear cells and leukemia lines of man and mouse

Regulation of the L‐arginine‐dependent and tetrahydrobiopterin‐dependent biosynthesis of nitric oxide in murine macrophages

Neopterin as an endogenous antioxidant

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