Dexamethasone But Not Indomethacin Inhibits Human Phagocyte Nicotinamide Adenine Dinucleotide Phosphate Oxidase Activity by Down-Regulating Expression of Genes Encoding Oxidase Components

摘要

We investigated the effects of dexamethasone or indomethacin on the NADPH oxidase activity, cytochrome b 558 content, and expression of genes encoding the components gp91- phox and p47- phox of the NADPH oxidase system in the human monocytic THP-1 cell line, differentiated with IFN-γ and TNF-α, alone or in combination, for up to 7 days. IFN-γ and TNF-α, alone or in combination, caused a significant up-regulation of the NADPH oxidase system as reflected by an enhancement of the PMA-stimulated superoxide release, cytochrome b 558 content, and expression of gp91- phox and p47- phox genes on both days 2 and 7 of cell culture. Noteworthy was the tremendous synergism between IFN-γ and TNF-α for all studied parameters. Dexamethasone down-regulated the NADPH oxidase system of cytokine-differentiated THP-1 cells as assessed by an inhibition on the PMA-stimulated superoxide release, cytochrome b 558 content, and expression of the gp91- phox and p47- phox genes. The nuclear run-on assays indicated that dexamethasone down-regulated the NADPH oxidase system at least in part by inhibiting the transcription of gp91- phox and p47- phox genes. Indomethacin inhibited only the PMA-stimulated superoxide release of THP-1 cells differentiated with IFN-γ and TNF-α during 7 days. None of the other parameters was affected by indomethacin. We conclude that dexamethasone down-regulates the NADPH oxidase system at least in part by inhibiting the expression of genes encoding the gp91- phox and p47- phox components of the NADPH oxidase system.