Influence of cytokines on multidrug resistance transporters in human hepatoma cell lines

Overexpression of P-Glycoprotein (PGP) and Multidrug Resistance Proteins (MRP) is a principle mechanism of drug resistance. Previously our laboratory demonstrated a down-regulation in hepatic PGP expression and activity in endotoxin and Interleukin-6 (IL-6) treated rodents. We therefore examined the effect of IL-6, IL-1β and TNF-α on PGP and MRP expression and activity in human hepatoma cell lines, (HuH7 and HepG2). Treatment of HuH7 cells with IL-6, IL-1β or TNF-α decreased the expression and activity of PGP while causing an induction of MRP3 at the level of mRNA. In HepG2 cells, PGP expression and activity was down-regulated upon IL-1β or TNF-α treatments, but not with IL-6. HepG2 cells treated with IL-6 or IL-1β also expressed higher MRP1 mRNA levels while a decrease in MRP1 and MRP3 expression was seen with TNF-α We conclude that these cytokines may play a role in the regulation of these transporters.