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IDO1 is an Integral Mediator of Inflammatory Neovascularization.

ABSTRACT: The immune tolerogenic effects of IDO1 (indoleamine 2,3-dioxygenase 1) have been well documented and genetic studies in mice have clearly established the significance of IDO1 in tumor promotion. Dichotomously, the primary inducer of IDO1, the inflammatory cytokine IFN? (interferon-?), is a key mediator of immune-based tumor suppression. One means by which IFN? can exert an anti-cancer effect is by decreasing tumor neovascularization. We speculated that IDO1 might contribute to cancer promotion by countering this anti-neovascular effect of IFN?, possibly through IDO1-potentiated elevation of the pro-tumorigenic inflammatory cytokine IL6 (interleukin-6). In this study, we investigated how genetic loss of IDO1 affects neovascularization in mouse models of oxygen-induced retinopathy and lung metastasis. Neovascularization in both models was significantly reduced in mice lacking IDO1, was similarly reduced with loss of IL6, and was restored in both cases by concomitant loss of IFN?. Likewise, the lack of IDO1 or IL6 resulted in reduced metastatic tumor burden and increased survival, which the concomitant loss of IFN? abrogated. This insight into IDO1's involvement in pro-tumorigenic inflammatory neovascularization may have important ramifications for IDO1 inhibitor development, not only in cancer where clinical trials are currently ongoing, but in other disease indications associated with neovascularization as well.

SUBMITTER: Mondal A

PROVIDER: S-EPMC5161421 | biostudies-other | 2016 Dec

REPOSITORIES: biostudies-other

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IDO1 is an Integral Mediator of Inflammatory Neovascularization.

Mondal Arpita A Smith Courtney C DuHadaway James B JB Sutanto-Ward Erika E Prendergast George C GC Bravo-Nuevo Arturo A Muller Alexander J AJ

EBioMedicine 20161109

The immune tolerogenic effects of IDO1 (indoleamine 2,3-dioxygenase 1) have been well documented and genetic studies in mice have clearly established the significance of IDO1 in tumor promotion. Dichotomously, the primary inducer of IDO1, the inflammatory cytokine IFNγ (interferon-γ), is a key mediator of immune-based tumor suppression. One means by which IFNγ can exert an anti-cancer effect is by decreasing tumor neovascularization. We speculated that IDO1 might contribute to cancer promotion b ...[more]

PMID: 27889479

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Project description:ObjectiveTo investigate the correlations between aqueous concentrations of interleukin 1?, 6, 8, 10, 12p (IL-1?, IL-6, IL-8, IL-10, IL-12p), and tumor necrosis factor ? (TNF-?) and the parameters of macular edema acquired by optical coherence tomography (OCT) in patients with choroidal neovascularization.MethodsIL-1?, IL-6, IL-8, IL-10, IL-12p, and TNF-? in the aqueous humor samples of 17 patients with exudative age-related macular degeneration (AMD), ten patients with pathological myopia (PM), seven patients with idiopathic choroidal neovascularization (CNV), and 14 patients with cataract and idiopathic epiretinal membrane or macular hole in the control group were measured with cytometric bead array. The maximum macular thickness and macular volume within 1 mm, 3 mm, and 6 mm were measured with OCT.ResultsIn the CNV groups, the aqueous levels of IL-6 and IL-8 were significantly associated with macular volume within 6 mm (p=0.011, p=0.008, respectively), while IL-1?, IL-10, IL-12p, and TNF-? showed no significant correlation with either the maximum macular thickness or the macular volume. By further selecting patients with CNV who had accepted their last intravitreal injection of bevacizumab within 3 months, the level of IL-6 still significantly correlated with the maximum macular thickness (p=0.019) and macular volume within 1 mm (p=0.018), 3 mm (p=0.018), and 6 mm (p=0.022). In patients with exudative AMD, the level of IL-6 was significantly associated with the maximum macular thickness (p=0.025) and macular volume within 1 mm (p=0.025), 3 mm (p=0.006), and 6 mm (p=0.002). The aqueous level of all cytokines did not vary significantly between the CNV patients who had accepted their last intravitreal injection of bevacizumab within 3 months and the other patients, nor was a difference found among patients with exudative AMD, PM, and idiopathic CNV, and the control group.ConclusionsIntraocular concentrations of IL-6 and IL-8 (particularly IL-6) are significantly associated with the volume of macular edema in patients with CNV. However, intravitreal injection of antivascular endothelial growth factor drugs did not change the intraocular level of these inflammation cytokines.

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IDO1 is an Integral Mediator of Inflammatory Neovascularization.

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IDO1 is an Integral Mediator of Inflammatory Neovascularization.

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