Dexamethasone inhibits nitric oxide-mediated cytotoxicity via effects on both macrophages and target cells.
In order to evaluate the mode of action of dexamethasone (DEX) on macrophage-mediated cytotoxicity and to understand its association with nitric oxide (NO) production, the effect of DEX on macrophage- and spermine NONOate-mediated cytotoxicity was studied. DEX caused 100% inhibition of cytotoxicity by LPS- and IFN gamma-activated macrophages whereas it caused only partial inhibition of NO production. Inhibition of macrophage-mediated cytotoxicity by DEX was not reversed by supplementation of rTNF alpha. The partial inhibition of NO production by DEX was due to partial inhibition of iNOS mRNA expression. Incubation of macrophages with DEX for up to 24 h prior to activation did not cause further inhibition of NO production. DEX failed to inhibit NO production if added 6 h after addition of LPS and IFN gamma. Addition of P815 cells after the onset of NO production resulted in partial restoration of cytotoxicity in DEX-treated macrophages. Incubation of P815 cells with spermine NONOate, a synthetic NO donor, resulted in P815 cell lysis, which was dose-dependent, had a lag phase of 3 h and was blocked by hemoglobin. DEX also inhibited spermine NONOate-mediated tumor cell lysis, indicating that DEX may have a protective effect on tumor targets. These results indicate that DEX inhibits macrophage-mediated cytotoxicity by decreasing NO production and by inhibiting the cytotoxic effects of NO on the target cells.
Department of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical Center, Kansas City 66160, USA.
Y
Y
Li
N
N
Ito
T
T
Suzuki
D J
DJ
Stechschulte
K N
KN
Dileepan
D000818:Animals; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D003907:Dexamethasone / Q000494:pharmacology*; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000235:genetics; D009589:Nitrogen Oxides; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins; D013096:Spermine / Q000031:analogs & derivatives / Q000378:metabolism; D014407:Tumor Cells, Cultured
D008070:Lipopolysaccharides; D009589:Nitrogen Oxides; D012333:RNA, Messenger; D011994:Recombinant Proteins; C091861:spermine nitric oxide complex; D013096:Spermine; D009569:Nitric Oxide; D003907:Dexamethasone; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase