Nitric oxide attenuates beryllium-induced IFNgamma responses in chronic beryllium disease: evidence for mechanisms independent of IL-18.
In chronic beryllium disease (CBD), a granulomatous lung disease characterized by hypersensitivity to beryllium salts (BE), BE challenge of bronchoalveolar lavage cells induces IFNgamma. Although nitric oxide (NO) is elevated in CBD airways, the effects of NO on CBD IFNgamma responses are unknown. Here we report that BE-stimulated IFNgamma production in CBD lavage cells was markedly reduced (74%) by the NO generator DETA NONOate. Investigation of IFNgamma-stimulatory cytokine involvement indicated that lavage cell IL-18 was significantly increased (fourfold) by BE and reduced (64%) by DETA NONOate but IL-12 was undetectable. IL-18 production was caspase-1-dependent but caspase 1 inhibition reduced IFNgamma only partially (43%). Specific antibody depletion of lavage cell IL-18 yielded marginal reduction (19%) of IFNgamma. Data are the first to show that: (1) BE stimulates IL-18 as well as IFNgamma in CBD; (2) BE cytokine responses are NO-sensitive; and (3) NO down-regulation of IFNgamma involves other sites in addition to IL-18.
Barna
Barbara P
BP
Department of Pulmonary and Critical Care Medicine, The Cleveland Clinic Foundation, Ohio 44195, USA.
Dweik
Raed A
RA
Farver
Carol F
CF
Culver
Daniel
D
Yen-Lieberman
Belinda
B
Thomassen
Mary Jane
MJ
D001607:Berylliosis / Q000276:immunology* / Q000378:metabolism; D001608:Beryllium / Q000276:immunology / Q000633:toxicity*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D016022:Case-Control Studies; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000096:biosynthesis*; D020382:Interleukin-18 / Q000096:biosynthesis; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018448:Models, Immunological; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009603:Nitroso Compounds / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D015398:Signal Transduction
D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D020382:Interleukin-18; D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; D009842:Oligopeptides; C096429:L 709049; C094210:2,2'-(hydroxynitrosohydrazono)bis-ethanamine; D009569:Nitric Oxide; D007371:Interferon-gamma; D001608:Beryllium