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Dexamethasone But Not Indomethacin Inhibits Human Phagocyte Nicotinamide Adenine Dinucleotide Phosphate Oxidase Activity by Down-Regulating Expression of Genes Encoding Oxidase Components¹

Antonio Condino-Neto^*, Constance Whitney and Peter E. Newburger^2,

^* Center for Investigation in Pediatrics, State University of Campinas Medical School, Campinas, Brazil; and Department of Pediatrics and the Cancer Center, University of Massachusetts Medical Center, Worcester, MA 01655

We investigated the effects of dexamethasone or indomethacin on the NADPH oxidase activity, cytochrome b₅₅₈ 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- and TNF-, alone or in combination, for up to 7 days. IFN- and TNF-, 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 b₅₅₈ 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- and TNF- 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 b₅₅₈ 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- and TNF- 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.

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