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

Abstract

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.

Tetrahydrobiopterin Compounds Prolong Allograft Survival Independently of Their Effect on Nitric Oxide Synthase Activity

“…This suggests that the tetrahydrobiopterin compounds may exert their effect primarily on the posttranscriptional level. Consistent with this suggestion we found that in cultured murine bone marrow derived dendritic cells 4-amino tetrahydrobiopterin suppresses expression of MHC class II antigen and T-cell stimulatory capacity without affecting MHC class II mRNA levels in the cells (33). Interestingly, these effects were even more pronounced in cells from iNOS (-,-) mice (33).…”

Sepiapterin Decreases Acute Rejection and Apoptosis in Cardiac Transplants Independently of Changes in Nitric Oxide and Inducible Nitric-Oxide Synthase Dimerization

“…This does not exclude the possibility that sepiapterin improved rejection by some other redundant gene pathway. An intriguing possibility for the antirejection mechanism of sepiapterin is via an effect on T-cell function (Thoeni et al, 2005). In this context, we showed that sepiapterin decreased IL-2 expression, an important product of T-cell activation and a growth factor for T cells.…”

Tetrahydrobiopterin compounds modulate intracellular signaling and reactive oxygen species levels in an in vitro model of ischemia-reperfusion injury

“…ABH 4 could effectively induce apoptosis in T cells as well as in murine macrophages [21,50]. Our data demonstrate that high concentrations of ABH 4 present for longer periods of time cause a significant amount of cell death in HL-1 cardiomycoytes.…”

“…Inhibition of iNOS, however, did not account for the aforementioned protective effects of ABH 4 seen during acute rejection, as these occurred independently of the iNOS-inhibitory effect of ABH 4 [14]. Additionally, ABH 4 exhibited immunosuppressive effects, which did not relate to the iNOS-inhibiting properties of the compound either [21].…”