Hepatic cytochrome P450 down-regulation during aseptic inflammation in themouse is interleukin 6 dependent

Expression of cytochromes P450 (CYP) is markedly reduced during inflammator y processes. In vitro studies with hepatocytes have shown that cytokines ge nerated during these processes down-regulate CYP However, it is not clear t o what extent each individual cytokine contributes to the overall reduced e xpression of the various CYP isoenzymes in vivo. Interleukin 6 (IL-6), a ma jor player during inflammatory processes, is recognized as the most importa nt cytokine modulating the hepatic expression of acute-phase protein (APP) genes. For this reason, we selected the IL-6(-/-) mouse as a model to inves tigate the role of IL-6 in the down-regulation of hepatic CYP during experi mental inflammation. Our results show that the reduction in messenger RNA ( mRNA) levels of CYP1A2, CYP2A5, and CYP3A11 during turpentine-induced infla mmation was abrogated in IL-6-deficient mice, confirming that IL-6 is an in dispensable player for the down-regulation of hepatic CYP during aseptic in flammation, Moreover, the different CYP isoenzymes showed a variable grade of dependence on IL-6, CYP2A5 being the most sensitive one. In the case of CYP2E1, differences between IL-6-/- and wild-type mice were no longer maint ained after 24 hours, suggesting a delayed, rather than abrogated, CYP down regulation in the absence of IL-6. As opposed to that, hepatic CYP repressi on took place in IL-6-deficient mice during lipopolysaccharide (LPS)-mediat ed inflammation. This contrasting behavior observed for CYP is surprisingly similar to the one seen for extracellular (serum amyloid A, P-fibrinogen) and intracellular (metallothionein-l) APPs and points to the fact that, in the model of bacterial inflammation (LPS), the effects of IL-6 on CYP downr egulation are likely to be substituted by other cytokines or mediators.