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 and MRP) in human hepatoma cell lines. Expression and activity of MDR1 and MRP transporters were examined in IL-6-treated and control HuH 7 and HepG2 cells using semi-quantitative RT-PCR analysis and by rhodamine 123 and 5-carboxyfluorescin efflux assays. Results from RT-PCR demonstrated expression of MRP3, MRP6, and MDR1 in HuH 7 cells and expression of MRP1, MRP2, MRP3, MRP6, and MDR1 in HepG2 cells. Compared with controls, treatment of HuH 7 cells with IL-6 (10 ng/mL, 24 h) resulted in a 1.8-fold increase in MRP-mediated efflux of 5-CF with a corresponding 1.5-fold induction of MRP3 mRNA levels (p < 0.05). Similarly, in HepG2 cells, a 2-fold increase in MRP functional activity and a 1.8-fold induction of MRP1 mRNA levels were seen in the IL-6 treated cells (p < 0.05). Treatment of cells with IL-6 was also found to cause significant reductions in the expression and activity of MDR1 in HuH 7 cells, but not in HepG2 cells. Our data suggest that IL-6 induces MRP expression and activity in human hepatoma cell lines. Suppressive effects of IL-6 on MDR1 expression and activity were also observed in HuH 7 cells. This underscores the importance of examining the regulation of multiple drug resistance proteins as these proteins may have opposing regulatory mechanisms in malignant cells.
Lee
G
G
Faculty of Pharmacy, University of Toronto, ON, Canada.
Piquette-Miller
M
M
D001798:Blood Proteins / Q000378:metabolism; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D018432:Drug Resistance, Multiple / Q000235:genetics / Q000502:physiology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics / Q000502:physiology*; D005452:Fluoresceins; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019450:Genes, MDR / Q000235:genetics / Q000502:physiology*; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D011868:Radioisotopes; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012238:Rhodium; D014407:Tumor Cells, Cultured
D001798:Blood Proteins; D016207:Cytokines; D005452:Fluoresceins; D015850:Interleukin-6; D012333:RNA, Messenger; D011868:Radioisotopes; C045132:4-carboxyfluorescein; D012238:Rhodium