Tetrahydropteridines suppress gene expression and induce apoptosis of activated RAW264.7 cells via formation of hydrogen peroxide

Thoeni, Guntram; Werner, Ernst R.; Werner-Felmayer, Gabriele

doi:10.1016/j.freeradbiomed.2004.05.010

Cited by 16 publications

(20 citation statements)

References 38 publications

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“…For detection of H 4 -aminobiopterin and its oxidation products, a protocol recently detailed in Ref. 20 using MnO 2 oxidation, was used. Samples were then analyzed by HPLC (20).…”

Section: Determination Of Pteridines and Nitrite Plus Nitratementioning

confidence: 99%

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Tetrahydro-4-Aminobiopterin Attenuates Dendritic Cell-Induced T Cell Priming Independently from Inducible Nitric Oxide Synthase

Thoeni

Stoitzner

Brandacher

et al. 2005

The Journal of Immunology

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Formation of NO by NO synthases (NOSs) strictly depends on tetrahydrobiopterin. Its structural analog, tetrahydro-4-aminobiopterin, is an inhibitor of all NOS isoenzymes, which prolongs allograft survival in acute murine cardiac rejection and prevents septic shock in the rat. In this study, we show that murine bone marrow-derived dendritic cells treated with tetrahydro-4-aminobiopterin had a reduced capacity to prime alloreactive murine T cells in oxidative mitogenesis. Checking for a possible influence on LPS-induced dendritic cell maturation, we found that tetrahydro-4-aminobiopterin down-regulated MHC class II expression and counteracted LPS-induced down-regulation of ICOS ligand, while expression of CD40, CD86, CD80, B7-H1, and B7-DC remained unchanged. Tetrahydro-4-aminobiopterin also reduced activation of CD4+ T cells isolated from mice overexpressing an OVA-specific TCR by OVA-loaded murine bone marrow-derived dendritic cells, thus indicating that its effect on MHC class II expression is involved in attenuating T cell activation. In line with affecting dendritic cell function and T cell activation, tetrahydro-4-aminobiopterin impaired production of proinflammatory cytokines and the Th1 response. With regard to cell survival, tetrahydro-4-aminobiopterin induced efficient apoptosis of murine T cells but not of murine dendritic cells. Experiments with cells from inducible NOS (iNOS) knockout mice and with N6-(1-iminoethyl)-l-lysine, a specific inhibitor of iNOS, ruled out participation of iNOS in any of the observed effects. These findings characterize attenuation of T cell stimulatory capacity of murine bone marrow-derived dendritic cells as an immunosuppressive mechanism of tetrahydro-4-aminobiopterin that is not related to its iNOS-inhibiting properties.

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“…For detection of H 4 -aminobiopterin and its oxidation products, a protocol recently detailed in Ref. 20 using MnO 2 oxidation, was used. Samples were then analyzed by HPLC (20).…”

Section: Determination Of Pteridines and Nitrite Plus Nitratementioning

confidence: 99%

“…20 using MnO 2 oxidation, was used. Samples were then analyzed by HPLC (20). Nitrite plus nitrate were quantified by reversed phase HPLC equipped with a cadmium reactor to reduce nitrate to nitrite and postcolumn detection of nitrite by the Griess reaction as outlined previously (20).…”

Section: Determination Of Pteridines and Nitrite Plus Nitratementioning

confidence: 99%

Tetrahydro-4-Aminobiopterin Attenuates Dendritic Cell-Induced T Cell Priming Independently from Inducible Nitric Oxide Synthase

Thoeni

Stoitzner

Brandacher

et al. 2005

The Journal of Immunology

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“…BH4 auto-oxidation could produce hydrogen peroxide and superoxide radical [18][19][20][21]. In addition, DA, with its synthesis facilitated by BH4, in turn undergoes auto-oxidation to form a reactive quinine species [18,22,24].…”

Section: Discussionmentioning

confidence: 99%

“…It has been demonstrated that BH4 and DA together lead to generation of oxidative stress and render DA cells particularly vulnerable [16] and furthermore administration of BH4 to animals leads to as selective degeneration of the DA system [17]. BH4 itself generates oxidative stress by undergoing auto-oxidation [18][19][20][21] and elicits the formation of reactive quinonoid derivatives of DA and protein as well as lipid peroxidation in DA cells [22]. The amount of BH4 synthesizing enzyme, GTP cyclohydrolase I (GTP-CH I), is lowest, suggesting that the level of BH4 in this area might be normally subtoxic [23,24].…”

Section: Introductionmentioning

confidence: 99%

Alteration of striatal tetrahydrobiopterin in iron-induced unilateral model of Parkinson's disease

Aryal

2016

Parkinsonism & Related Disorders

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It has been suggested that transition metal ions such as iron can produce an oxidative injuries to nigrostriatal dopaminergic neurons, like Parkinson's disease (PD) and subsequent compensative increase of tetrahydrobiopterin (BH4) during the disease progression induces the aggravation of dopaminergic neurodegeneration in striatum. It had been established that the direct administration of BH4 into neuron would induce the neuronal toxicity in vitro. To elucidate a role of BH4 in pathogenesis in the PD in vivo, we assessed the changes of dopamine (DA) and BH4 at striatum in unilateral intranigral iron infused PD rat model. The ipsistriatal DA and BH4 levels were significantly increased at 0.5 to 1 d and were continually depleting during 2 to 7 d after intranigral iron infusion. The turnover rate of BH4 was higher than that of DA in early phase. However, the expression level of GTPcyclohydrolase I mRNA in striatum was steadily increased after iron administration. These results suggest that the accumulation of intranigral iron leads to generation of oxidative stress which damage to dopaminergic neurons and causes increased release of BH4 in the dopaminergic neuron. The degenerating dopaminergic neurons decrease the synthesis and release of both BH4 and DA in vivo that are relevance to the progression of PD. Based on these data, we propose that the increase of BH4 can deteriorate the disease progression in early phase of PD, and the inhibition of BH4 increase could be a strategy for PD treatment.

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“…Only recently, the formation of superoxide by reaction of tetrahydrobiopterin with molecular oxygen was confirmed and the reduced pterin was discussed as a physiologic prooxidant under conditions of its overproduction (5) or exogenous administration in cell culture (6). Moreover, a trihydrobiopterin radical was proposed to occur as a reaction intermediate.…”

Section: Tetrahydropterinsmentioning

confidence: 99%

Modulation of Free Radical Formation by Pterin Derivatives

Oettl¹,

Greilberger²,

Reibnegger³

2004

Pteridines

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All classes of pterins, fully reduced tetrahydropterins, aromatic pterins and dihydropterins have been investigated upon their effects on radical mediated reactions. Meanwhile all these classes were shown to act as both, proand antioxidants by a number of different methods including chemical, biochemical and biological systems. From reduced pterins radicals including oxygen-, nitrogen-and pterin-radicals arc formed enzymatically and non-enzymatically, reduced pterins react with free radicals and serve as reductive agents. All classes of pterins may interfere with enzymes involved in radical formation. Upon the diversity of possibilities the net effect of a particular compound is a question of the experimental settings and the physiological relevant role often remains obscure.

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Tetrahydropteridines suppress gene expression and induce apoptosis of activated RAW264.7 cells via formation of hydrogen peroxide

Cited by 16 publications

References 38 publications

Tetrahydro-4-Aminobiopterin Attenuates Dendritic Cell-Induced T Cell Priming Independently from Inducible Nitric Oxide Synthase

Tetrahydro-4-Aminobiopterin Attenuates Dendritic Cell-Induced T Cell Priming Independently from Inducible Nitric Oxide Synthase

Alteration of striatal tetrahydrobiopterin in iron-induced unilateral model of Parkinson's disease

Modulation of Free Radical Formation by Pterin Derivatives

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