Journal
BLOOD
Volume 116, Issue 10, Pages 1755-1760Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2009-07-233734
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Funding
- National Institute of Allergy and Infectious Diseases Division of Intramural Research
- Clinical Center of the National Institutes of Health (NIH)
- National Cancer Institute, NIH [HHSN261200800001E]
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In chronic granulomatous disease (CGD), defective phagocytic nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity causes reduced superoxide anion (O(2)(sic)) radical production leading to frequent infections as well as granulomas and impaired wound healing indicative of excessive inflammation. Based on recent mouse studies, the lack of O(2)(radical anion)-dependent interferon gamma (IFN gamma)-induced synthesis of kynurenine (kyn), an anti-inflammatory tryptophan metabolite produced by indolamine 2,3 deoxygenase (IDO), was proposed as a cause of hyperinflammation in CGD and this pathway has been considered for clinical intervention. Here, we show that IFN gamma induces normal levels of kynurenine in cultures of O(2)(radical anion)-deficient monocytes, dendritic cells, and polymorphonuclear leukocytes from gp91(PHOX)- or p47(PHOX)-deficient human CGD donors. Kynurenine accumulation was dose-and time-dependent as was that of a downstream metabolite, anthranilic acid. Furthermore, urinary and serum levels of kynurenine and a variety of other tryptophan metabolites were elevated rather than suppressed in CGD donors. Although we did not specifically evaluate kyn metabolism in local tissue or inflamed sites in humans, our data demonstrates that O(2)(radical anion) anion is dispensable for the rate-limiting step in tryptophan degradation, and CGD patients do not appear to have either hematopoietic cell or systemic deficits in the production of the anti-inflammatory kynurenine molecule. (Blood. 2010; 116(10):1755-1760)
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