Effects of upregulated indoleamine 2, 3-dioxygenase 1 by interferon γ gene transfer on interferon γ-mediated antitumor activity

Abstract

Interferon γ (IFN-γ), an anticancer agent, is a strong inducer of indoleamine 2,3-dioxygenase 1 (IDO1), which is a tryptophan-metabolizing enzyme involved in the induction of tumor immune tolerance. In this study, we investigated the IDO1 expression in organs after IFN-γ gene transfer to mice. IFN-γ gene transfer greatly increased the mRNA expression of IDO1 in many tissues with the highest in the liver. This upregulation was associated with reduced L-tryptophan levels and increased L-kynurenine levels in serum, indicating that IFN-γ gene transfer increased the IDO activity. Then, Lewis lung carcinoma (LLC) tumor-bearing wild-type and IDO1-knockout (IDO1 KO) mice were used to investigate the effects of IDO1 on the antitumor activity of IFN-γ. IFN-γ gene transfer significantly retarded the tumor growth in both strains without any significant difference in tumor size between the two groups. By contrast, the IDO1 activity was increased only in the wild-type mice by IFN-γ gene transfer, suggesting that cells other than LLC cells, such as tumor stromal cells, are the major contributors of IDO1 expression in LLC tumor. Taken together, these results imply that IFN-γ gene transfer mediated IDO1 upregulation in cells other than LLC cells has hardly any effect on the antitumor activity of IFN-γ.

Inhibition of the aryl hydrocarbon receptor prevents Western diet-induced obesity. Model for AHR activation by kynurenine via oxidized-LDL, TLR2/4, TGFβ, and IDO1

“…Ido1 −/− mice showed an even greater drop in the plasma Kyn/Trp ratio as well as a resistance to obesity (Nagano et al , 2013). Thus, IDO1, like its many roles in immune cell regulation, may be the key regulator of systemic Kyn levels in the context of obesity and obesity-associated inflammation (Watcharanurak et al , 2014), while the role of TDO2 in obesity and its regulation by glucocorticoids remain obscure (Poulain-Godefroy et al , 2013) and need to be explored further.…”

Presentation of hepatocellular antigens

“…IFN-β induces the enzyme IDO1, which imposes T-cell tolerance though the depletion of tryptophan and the synthesis of kynurenine. 51 IFN-γ gene transduction also induces the Ido1 gene 52 as well as both Fas (CD95) and Fas ligand, 53 the interaction of which results in T-cell apoptosis. Some other proinflammatory cytokines have similar effects.…”

Overexpression of indoleamine 2, 3‑dioxygenase contributes to the repair of human airway epithelial cells inhibited by dexamethasone via affecting the MAPK/ERK signaling pathway

“…IDO widely distributed in the tissues of humans and other mammals ( 21 ), including lung, neuroglia, endothelial cells, and visceral epithelial cells ( 22 – 25 ). And the secretion of IDO is impacted by lipopolysaccharide, cytokines, tumor necrosis factor-α (TNF-α), and interferon γ (IFN-γ) ( 26 ). It has been demonstrated that the IDO transcriptional induction is the mechanism of neuroendocrine disorders triggered by chronic inflammation ( 27 ).…”