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

During inflammation and infection, overexpression of cytokines is asso ciated with changes in cytochrome P450 (CYP) activities. The present s tudy investigated the effect of cytokines on expression of the glutath ione S-transferases (GST), phase II enzymes, involved in drug detoxica tion and in protection against lipid peroxidation. Human hepatocytes i n primary culture were exposed to interleukin 6 (IL6), a proinflammato ry cytokine and interleukin 4 (IL4) thought to be an anti-inflammatory cytokine and known to induce CYP2E1 specifically. After a three-day t reatment, no reproducible effects of IL-6 could be demonstrated on eit her GSTA1 and/or A2 or M1 mRNA levels (GSTA1 and A2 were not discrimin ated 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 transcr iption is necessary and was associated with increased AP1 binding acti vities. These results provide evidences that IL4 exerts important effe cts on detoxifying hepatic drug metabolizing enzymes. (C) 1995 Academi c Press, Inc. .