Dexamethasone (DEX) is a well-known inhibitor of tumor necrosis factor (TNF) production when given shortly before lipopolysaccharide (LPS). However, DEX (10 mg/kg, ip) potentiates TNF production when administered 24-48 hr before LPS (16 micrograms/kg, ip). We have found that this is probably due to DEX induction of cytochrome P450 3A, which is known to produce nitric oxide (NO). The upregulating effect of DEX on TNF production is associated with increased NO production. Both the upregulation of NO and of TNF production by DEX are inhibited by co-administration of the P450 3A inhibitor troleandomycin (TAO, 40 mg/kg, ip). These data suggest that P450 3A-generated NO might be involved in TNF induction.