Tryptophan/kynurenine metabolism in human leukocytes is independent of superoxide and is fully maintained in chronic granulomatous disease.
In chronic granulomatous disease (CGD), defective phagocytic nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity causes reduced superoxide anion (O(2)(·)) 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)(·)-dependent interferon γ (IFNγ)-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 IFNγ induces normal levels of kynurenine in cultures of O(2)(·)-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)(·) 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.
De Ravin
Suk See
SS
Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. sderavin@niaid.nih.gov
Zarember
Kol A
KA
Long-Priel
Debra
D
Chan
King C
KC
Fox
Stephen D
SD
Gallin
John I
JI
Kuhns
Douglas B
DB
Malech
Harry L
HL
D002478:Cells, Cultured; D002853:Chromatography, Liquid; D004305:Dose-Response Relationship, Drug; D006105:Granulomatous Disease, Chronic / Q000097:blood / Q000235:genetics / Q000652:urine; D006801:Humans; D015151:Immunoblotting; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D007700:Kinetics; D007737:Kynurenine / Q000378:metabolism*; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000172:deficiency / Q000235:genetics; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization; D013481:Superoxides / Q000378:metabolism*; D013997:Time Factors; D014364:Tryptophan / Q000378:metabolism* / Q000652:urine
D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D008562:Membrane Glycoproteins; D013481:Superoxides; D007737:Kynurenine; D007371:Interferon-gamma; D014364:Tryptophan; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1