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Dexamethasone Modulation of In Vivo Effects of Endotoxin, Tumor Necrosis Factor, and Interleukin‐1 on Liver Cytochrome P‐450, Plasma Fibrinogen, and Serum Iron
Author(s) -
Bertini Riccardo,
Bianchi Marina,
Erroi Annalaura,
Villa Pia,
Ghezzi Pietro
Publication year - 1989
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1002/jlb.46.3.254
Subject(s) - in vivo , tumor necrosis factor alpha , endocrinology , medicine , lipopolysaccharide , biology , interleukin , cytochrome , dexamethasone , fibrinogen , cytokine , biochemistry , enzyme , microbiology and biotechnology
Abstract Treatment of mice with endotoxin (lipopolysaccharide, LPS) and the two LPS‐induced monokines, tumor necrosis factor (TNF) and interleukin‐1 (IL‐1), 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. However, only IL‐1, not TNF or LPS, depressed cytochrome P‐450 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‐1 antiserum, and its synthesis, like that of IL‐1, 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‐1, suggesting that IL‐1 directly depresses cytochrome P‐450 and that DEX acts by inhibiting IL‐1 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‐1. Therefore, the effect of DEX in vivo, although supporting the hypothesis that depression of liver cytochrome P‐450 by LPS and TNF is mediated by IL‐1, indicates the existence of IL‐1‐independent pathways in the acute‐phase response.