Search

The naturally occurring stilbenoid oxyresveratrol was shown to influence inflammatory and metabolic processes. During cellular immune activation, tryptophan breakdown and neopterin formation via the enzymes indoleamine 2,3-dioxygenase-1 (IDO-1) and GTP-cyclohydrolase, respectively, are induced. Neopterin and the kynurenine to tryptophan ratio are reliable and pertinent biomarkers of Th1-type immune response and are also used in vitro to monitor effects of active plant ingredients on peripheral blood mononuclear cells (PBMCs). We investigated the effects of oxyresveratrol on the activity of the above-mentioned pathways in mitogen-stimulated human PBMC and in the myelomonocytic cell line THP-1. Oxyresveratrol exerted suppressive effects on tryptophan breakdown in both stimulated cell models. Of note, in PBMC, tryptophan breakdown was induced at lower concentrations (5–20 µM) and suppressed at higher treatment concentrations only. Neopterin formation was decreased dose-dependently in stimulated PBMC. In unstimulated PBMC similar, albeit lesser effects were observed. Data indicate that oxyresveratrol exerts distinct and concentration-dependent effects on different immune cell types. IDO-1 is targeted by oxyresveratrol and its activity can be modulated in both directions. Detailed investigations of the interactions would be interesting to fully explore the activity of this phytocompound.

Background: Interferon-γ (IFN- γ) regulates the degradation of tryptophan to kynurenine via induction of indoleamine- 2,3-dioxygenase (IDO). Local tryptophan depletion and accumulation of toxic metabolites might impair the proliferative capacity of lymphocytes. The aim of this study was to assess the actual status of immune system activation of patients with bacterial infection in the acute phase and during convalescence in vivo and in vitro. Parameters of systemic immune system activation were evaluated for associations with proliferative responsiveness of immune cells, and compared with healthy controls. Methods: 24 patients with various acute bacterial infections were included in the group of acutely ill patients. Sixteen patients participated in a follow-up examination after convalescence. The control group consisted of 6 healthy people. To assess the status of immune system activation in vivo, inflammation parameters C-reactive protein and differential blood counts were determined. Neopterin concentrations were measured by enzyme-linked immunosorbent assay (ELISA). Tryptophan and kynurenine measurements were performed with high pressure liquid chromatography (HPLC). Peripheral blood mononuclear cells (PBMCs) were isolated from the patients’ blood and stimulated with concanavalin A (Con A), phytohemagglutinin (PHA) and pokeweed mitogen (PWM) in vitro proliferation rates were evaluated by ³H-thymidine incorporation and neopterin production and tryptophan degradation were determined in supernatants of mitogen stimulated PBMCs. Results: Patients with acute bacterial infections showed reduced tryptophan and elevated neopterin concentrations, which did not normalize after convalescence period. Higher plasma neopterin values and increased IDO-activity were associated with reduced proliferative responses in vitro after stimulation with PHA. Associations were observed during acute infection as well as convalescence. Conclusions: Results of this study show that increased immune system activation in vivo is associated with impaired proliferative responsiveness of immune cells in vitro in acute bacterial infections as well as during convalescence.

In vitro, large amounts of neopterin are released from human monocyte-derived macrophages and dendritic cells primarily upon stimulation with Th1-type cytokine interferon-γ (IFN-γ). IFN-γ also induces the enzyme indoleamine 2,3-dioxygenase (IDO), which degrades tryptophan (TRP) to form kynurenine (KYN). IDO-mediated TRP catabolism is very effective in suppressing the proliferation of T lymphocytes as well as of pathogens in vitro and in vivo. In this study, we investigated whether exogenously added neopterin may influence IDO activity in resting and in stimulated peripheral blood mononuclear cells (PBMC). PBMC were isolated from healthy donors, and neopterin was added in a concentration range from 0.01 to 50 μmol/L. After 30 min, PBMC were stimulated or not with 10 μg/mL of mitogen phytohemagglutinin (PHA). After 48 h, culture supernatants were collected, KYN and TRP concentrations were measured by high-performance liquid chromatography, and the ratio of KYN vs. TRP was calculated as an estimate of IDO activity. Spontaneous as well as PHA-induced TRP breakdown was suppressed by exogenously added neopterin in a dose-dependent way; the lowest active concentration of neopterin was in vivo.