UP-REGULATION OF GLUTATHTONE S-TRANSFERASES-ALPHA BY INTERLEUKIN-4 IN HUMAN HEPATOCYTES IN PRIMARY CULTURE

During inflammation and infection, overexpression of cytokines is associated with changes in cytochrome P450 (CYP) activities. The present study investigated the effect of cytokines on expression of the glutathione S-transferases (GST), phase II enzymes, involved in drug detoxication and in protection against lipid peroxidation. Human hepatocytes in primary culture were exposed to interleukin 6 (IL6), a proinflammatory cytokine and interleukin 4 (IL4) thought to be an anti-inflammatory cytokine and known to induce CYP2E1 specifically. After a three-day treatment, no reproducible effects of IL-6 could be demonstrated on either GSTA1 and/or A2 or M1 mRNA levels (GSTA1 and A2 were not discriminated by the cDNA probe). In contrast, GSTA1 and/or A2 mRNAs and GSTA1 and A2 proteins were reproducedly increased after IL4 treatment. This increase was blocked by alpha-amanitin, suggesting that active transcription is necessary and was associated with increased AP1 binding activities. These results provide evidences that IL4 exerts important effects on detoxifying hepatic drug metabolizing enzymes. (C) 1995 Academic Press, Inc. .