Influence of IL-6 on MDR and MRP-mediated multidrug resistance in human hepatoma cells

The objective of this study was to examine effects of interleukin-6 (IL-6) on the expression and activity of the drug resistance transporters (MDR1 an d MRP) in human hepatoma cell lines. Expression and activity of MDR1 and MR P transporters were examined in IL-6-treated and control HuH 7 and HepG2 ce lls using semi-quantitative RT-PCR analysis and by rhodamine 123 and 5-carb oxyfluorescin efflux assays. Results from RT-PCR demonstrated expression of MRP3, MRP6, and MDR1 in HuH 7 cells and expression of MRP1, MRP2, MRP3, MR P6, and MDR1 in HepG2 cells. Compared with controls, treatment of HuH 7 cel ls with IL-6 (10 ng/mL, 24 h) resulted in a 1.8-fold increase in MRP-mediat ed efflux of 5-CF with a corresponding 1.5-fold induction of MRP3 mRNA leve ls (p < 0.05). Similarly, in HepG2 cells, a 2-fold increase in MRP function al activity and a 1.8-fold induction of MRP1 mRNA levels were seen in the I L-6 treated cells (p < 0.05). Treatment of cells with IL-6 was also found t o cause significant reductions in the expression and activity of MDR1 in Hu H 7 cells, but not in HepG2 cells. Our data suggest that IL-6 induces MRP e xpression and activity in human hepatoma cell lines. Suppressive effects of IL-6 on MDR1 expression and activity were also observed in HuH 7 cells. Th is underscores the importance of examining the regulation of multiple drug resistance proteins as these proteins may have opposing regulatory mechanis ms in malignant cells.