DEXAMETHASONE MODULATION OF INVIVO EFFECTS OF ENDOTOXIN, TUMOR NECROSIS FACTOR, AND INTERLEUKIN-1 ON LIVER CYTOCHROME-P-450, PLASMA-FIBRINOGEN, AND SERUM IRON

Treatment of mice with endotoxin (lipopolysaccharide, LPS) and the two LPS-induced monokines, tumor necrosis factor (TNF) and interleukin-1 (IL-i), caused a depression of liver cytochrome P-450 and related drug-metabolizing enzymes, as well as other acute- phase changes including increase in plasma fibrinogen levels and hypoferremia. How- ever, only IL-i , not TNF or LPS, depressed cytochrome P450 in cultured hepatocytes, suggesting that the effect of TNF in vivo might be mediated by a second mediator. TNF- or LPS-stimulated monocytes released a factor capable of depressing cytochrome P-450 in cultured hepatocytes. This factor was inhibited by anti-IL-i antiserum, and its synthe- sis, like that of IL-i , was inhibited by dexamethasone (DEX). Pretreatment of mice with DEX protected against the depression of liver cytochrome P-450 by LPS or TNF but not by IL-i , suggesting that IL-i directly depresses cytochrome P450 and that DEX acts by inhibiting IL-i synthesis in vivo induced by LPS or TNF. However, DEX did not inhibit two other effects of LPS and TNF in vivo: increase of plasma fibrinogen levels and decrease of plasma iron, suggesting that these might not be mediated by IL-i . Therefore, the effect of DEX in vivo, although supporting the hypothesis that depression of liver cytochrome P450 by LPS and TNF is mediated by IL-i, indicates the existence of IL-i-independent pathways in the acute-phase response.