DEXAMETHASONE INHIBITS NITRIC OXIDE-MEDIATED CYTOTOXICITY VIA EFFECTSON BOTH MACROPHAGES AND TARGET-CELLS

In order to evaluate the mode of action of dexamethasone (DEX) on macr ophage-mediated cytotoxicity and to understand its association with ni tric oxide (NO) production, the effect of DEX on macrophage-and spermi ne NONOate-mediated cytotoxicity was studied. DEX caused 100% inhibiti on of cytotoxicity by LPS-and IFN gamma-activated macrophages whereas it caused only partial inhibition of NO production. Inhibition of macr ophage-mediated cytotoxicity by DEX was not reversed by supplementatio n of rTNF alpha. The partial inhibition of NO production by DEX was du e to partial inhibition of iNOS mRNA expression. Incubation of macroph ages 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 a dded 6 h after addition of LPS and IFN gamma. Addition of P815 cells a fter the onset of NO production resulted in partial restoration of cyt otoxicity in DEX-treated macrophages. Incubation of P815 cells with sp ermine NONOate, a synthetic NO donor, resulted in P815 cell lysis, whi ch was dose-dependent, had a lag phase of 3 h and was blocked by hemog lobin. DEX also inhibited spermine NONOate-mediated tumor cell lysis, indicating that DEX may have a protective effect on tumor targets. The se results indicate that DEX inhibits macrophage-mediated cytotoxicity by decreasing NO production and by inhibiting the cytotoxic effects o f NO on the target cells.