title: Recombinant interferon gamma augments phagocyte superoxide production and X-chronic granulomatous disease gene expression in X-linked variant chronic granulomatous disease.
abstract: We examined the potential of interferon gamma (IFN-gamma) to ameliorate the physiologic defect of chronic granulomatous disease (CGD) by studying its effects on CGD phagocyte superoxide generation, NADPH oxidase kinetics, cytochrome b559 content, and expression of X-CGD (the gene for the X-linked disease). Granulocytes and macrophages from three patients in two kindreds with "variant" X-linked CGD (i.e., with very low, but detectable, baseline superoxide-generating activity) responded to IFN-gamma with enhanced nitroblue tetrazolium reduction and two- to eightfold increases in superoxide generation. IFN-gamma did not augment the respiratory burst activity of phagocytes from patients with "classic" CGD (i.e., no detectable baseline superoxide generation) or autosomal variant CGD. Incubation of a responding patient's granulocytes with IFN-gamma nearly doubled the maximal velocity for the NADPH oxidase, but did not change its abnormal Michaelis constant. Although the interferon-treated CGD granulocytes produced superoxide at a rate 40% of normal, the cytochrome b spectrum remained undetectable. IFN-gamma treatment of cultured monocytes from an IFN-gamma-responsive CGD patient increased the steady state level of RNA transcripts from the X-CGD gene from barely detectable up to approximately 5% of normal.
authors.affiliation: Division of Hematology/Oncology, Children's Hospital, Boston, Massachusetts 02115.
authors.forename: R A
authors.initials: RA
authors.lastname: Ezekowitz
authors.forename: S H
authors.initials: SH
authors.lastname: Orkin
authors.forename: P E
authors.initials: PE
authors.lastname: Newburger
mesh_terms: D003573:Cytochrome b Group / Q000378:metabolism; D005786:Gene Expression Regulation; D006098:Granulocytes / Q000187:drug effects / Q000378:metabolism; D006105:Granulomatous Disease, Chronic / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D007700:Kinetics; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D019255:NADPH Oxidases; D009580:Nitroblue Tetrazolium; D010101:Oxygen Consumption; D010586:Phagocytes / Q000187:drug effects / Q000378:metabolism*; D045332:Photosystem II Protein Complex; D011994:Recombinant Proteins / Q000494:pharmacology*; D013481:Superoxides / Q000096:biosynthesis*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: D003573:Cytochrome b Group; D045332:Photosystem II Protein Complex; D011994:Recombinant Proteins; D013481:Superoxides; D009580:Nitroblue Tetrazolium; D007371:Interferon-gamma; C019313:cytochrome b559; D009247:NADH, NADPH Oxidoreductases; D019255:NADPH Oxidases; D013755:Tetradecanoylphorbol Acetate