Nitric Oxide Attenuates Beryllium-Induced IFNγ 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 IFNγ. Although nitric oxide (NO) is elevated in CBD airways, the effects of NO on CBD IFNγ responses are unknown. Here we report that BE-stimulated IFNγ production in CBD lavage cells was markedly reduced (74%) by the NO generator DETA NONOate. Investigation of IFNγ-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 IFNγ only partially (43%). Specific antibody depletion of lavage cell IL-18 yielded marginal reduction (19%) of IFNγ. Data are the first to show that: (1) BE stimulates IL-18 as well as IFNγ in CBD; (2) BE cytokine responses are NO-sensitive; and (3) NO down-regulation of IFNγ involves other sites in addition to IL-18.