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Endotoxin tolerance aims at opposing hyperinflammatory responses to lipopolysaccharide (LPS) exposure. The aryl hydrocarbon receptor (AhR) participates in protection against LPS-mediated tissue damage, as it plays a necessary role in restraining the proinflammatory action of IL-1β and TNF-α while fostering the expression of protective TGF-β. TGF-β, in turn, promotes durable expression of the immune regulatory enzyme indoleamine 2,3-dioxygenase 1 (IDO1). IDO1 degrades L-tryptophan to L-kynurenine—an activating ligand for AhR—thus establishing a feed-forward loop. In this study, we further demonstrate that L-kynurenine also promotes the dissociation of the Src kinase–AhR cytosolic complex, leading to the activation of both genomic and non-genomic events in conventional dendritic cells (cDCs) primed with LPS. Specifically, the Src kinase, by phosphorylating the downstream target IDO1, triggers IDO1’s signaling ability, which results in enhanced production of TGF-β, an event key to establishing full endotoxin tolerance. We demonstrated that exogenous L-kynurenine can substitute for the effects of continued or repeated LPS exposure and that the AhR–Src–IDO1 axis represents a critical step for the transition from endotoxin susceptibility to tolerance. Moreover, much like fully endotoxin-tolerant dendritic cells (DCs) (i.e., treated twice with LPS in vitro), DCs—treated once with LPS in vitro and then with kynurenine—confer resistance on naïve recipients to an otherwise lethal LPS challenge. This may have clinical implications under conditions in which pharmacologically induced onset of endotoxin tolerance is a therapeutically desirable event.

Indoleamine 2,3-dioxygenase 1 (IDO1) is a cytosolic haem-containing enzyme involved in the degradation of tryptophan to kynurenine. Although initially thought to be solely implicated in the modulation of innate immune responses during infection, subsequent discoveries demonstrated IDO1 as a mechanism of acquired immune tolerance. In cancer, IDO1 expression/activity has been observed in tumor cells as well as in the tumor-surrounding stroma, which is composed of endothelial cells, immune cells, fibroblasts, and mesenchymal cells. IDO1 expression/activity has also been reported in the peripheral blood. This manuscript reviews available data on IDO1 expression, mechanisms of its induction, and its function in cancer for each of these compartments. In-depth study of the biological function of IDO1 according to the expressing (tumor) cell can help to understand if and when IDO1 inhibition can play a role in cancer therapy.

Immune system activation and inflammation accompanies immune dysfunction in trauma and sepsis patients. Tryptophan degradation via the kynurenine pathway by the cytokine-inducible enzyme indoleamine 2,3-dioxygenase (IDO) could contribute to the deficient responsiveness of immunocompetent cells. Activated IDO in patients after trauma and with sepsis is indicated by an increased kynurenine to tryptophan ratio (kyn/trp), which was found to be associated with poor outcome of patients. In this study, tryptophan and kynurenine concentrations in 18 patients post trauma or with sepsis during 12-14 days of follow up (up to 84 specimens were available) were compared to concentrations of neopterin and cytokines tumor necrosis factor-α (TNF-α) and interleukin- 6 (IL-6) and the in vitro response of lipopolysaccharide-stimulated monocytes. Compared to healthy controls, average kyn/trp and kynurenine, TNF-α, IL-6 and neopterin concentrations were increased in patients, and tryptophan concentrations were decreased. During follow-up, only kyn/trp, kynurenine and neopterin concentrations (all p s = 0.590; p s = 0.374; p s = 0.262; p

Nigella sativa, commonly known as black cumin seed, belongs to the botanical family of Ranunculaceae. The active antioxidant components of Nigella sativa display a remarkable array of biochemical, immunological and pharmacological actions, including bronchodilatory, anti-inflammatory, antibacterial, hypoglycaemic, antitumoural and immunopotentiating effects. Effects of Nigella sativa seeds extracts were investigated in freshly isolated human peripheral blood mononuclear cells stimulated with the mitogens phytohaemagglutinin and concanavalin A in vitro. Tryptophan degradation and neopterin production were monitored in culture supernatants, both these immunobiochemical pathways are induced by pro-inflammatory cytokine interferon-γ. Compared to unstimulated cells, the mitogens enhanced degradation of tryptophan and production of neopterin. Nigella sativa seeds extracts significantly suppressed both pathways in a dose-dependent way. Suppression of tryptophan degradation and neopterin formation by Nigella sativa seeds extracts demonstrates an inhibitory influence on activated T-cells and macrophages. Data are in line with an anti-inflammatory activity of the extracts.

Thl-type cytokine interferon-y induces neopterin production in human monocyte-derived macrophages and it stimulates enzyme indoleamine (2,3)-dioxygenase (IDO) which converts tryptophan to kynurenine in various cells. In an integrative single-case study, a healthy, 27-year-old female had collected her entire urine in 12-hour (= I lag) intervals on 56 consecutive days. Neopterin, tryptophan, kynurenine and Creatinine concentrations were determined using HPLC. The kynurenine to tryptophan ratio (kyn/trp) was calcuiated as an index for IDO activity. Within the Observation period, the woman experienced an infection episode presenting with vomiting and headache, however, not serologically verified. During this period, strong increases in both urinary kyn/trp and neopterin to Creatinine concentrations were observed, and thcrc was a significant correlation between neopterin/creatinine and kyn/trp at the same day (rs =0.334, p

Extract of traditional Tibetan herbal remedy Padma 28 revealed suppressive effects on neopterin production and tryptophan degradation in mitogen-stimulated peripheral blood mononuclear cells (PBMC). One of the questions was to asses the robustness of the Tibetan way of formulating herbal multicomponent medicines. Can small changes affect the effectiveness of the formula? In this study, effect of a derivative multicomponent mixture was investigated in stimulated and unstimulated human PBMC in vitro. Neopterin production and tryptophan degradation were measured in supernatants of PBMC in the presence or absence of mitogens phytohacmagglutinin and concanavalin A. Stimulation of PBMC induced neopterin formation and tryptophan degradation, and the herbal multicomponent mixture inhibited both immunobiochemical effects in a dose-dependent way. Higher concentrations were more effective and were able to completely block the pathways induccd upon mitogenic stimulation. When comparing the results obtained with those observed earlier using Padma 28, there was no obvious difference between the two different preparations. Data allow to conclude that Padma 28 and its modified version is equally able to suppress immunobiological effects in stimulated PBMC.