Intact indoleamine 2,3-dioxygenase activity in human chronic granulomatous disease

Abstract

Chronic granulomatous disease (CGD) is characterized by a disability to produce reactive oxygen intermediates (ROI) caused by a defect of phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. A hyperinflammatory response to immune activation has been reported to contribute to the pathology of CGD. The tryptophan catabolizing enzyme indoleamine 2,3-dioxygenase (IDO) is considered critical for regulating immune responses and suppression of inflammation. IDO is generally believed to require ROI for enzymatic activity and was found to be inactive in murine CGD. Here, we report that, strikingly, in human CGD IDO metabolic activity is intact. Monocyte-derived dendritic cells generated from CGD patients, harbouring X-linked and autosomal recessive forms of CGD, and from healthy controls produced similar amounts of the tryptophan metabolite kynurenine upon activation with lipopolysaccharide and interferon-γ. Thus, in humans, ROI apparently are dispensable for IDO activity. Hyperinflammation in human CGD cannot be attributed to disabled IDO activation.

Figure 1

Normal expression and activation of IDO in DCs of human CGD patients. (A) Recovery rate of DCs after activation with LPS/IFN-γ for 48 hours as healthy control derived DCs. (B) IDO immunoblotting; note that immunoblotting of immature DCs (iDC) was not possible due to low cell numbers obtained from patients 2–4. (C) kynurenine release into cell culture supernatants; gray bars, immature DCs; black bars, DCs activated with LPS/IFN-γ for 48 hours. co, control; pt, patient; KYN, kynurenine.