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.