Regulation of the hepatic multidrug resistance gene expression by endotoxin and inflammatory cytokines in mice.
P-glycoprotein (PGP), an ATP-dependent membrane transporter is found in epithelial tissues of the liver, kidneys, intestine and blood-brain barrier. In tumor cells, PGP is often overexpressed and confers multidrug resistance toward cancer chemotherapeutics. It has been previously shown in rats that induction of an inflammatory response evokes a decrease in hepatic expression of PGP. In order to identify the inflammatory mediators involved in this phenomenon, we examined the influence of experimentally induced inflammation and pro-inflammatory cytokines (interleukin (IL)-6, IL-1beta and tumor necrosis factor (TNF)-alpha) on the hepatic expression of PGP in mice. A significant reduction in the hepatic expression of mdr1a, mdr1b, mdr2 and spgp genes were seen in endotoxin (lipopolysaccharide (LPS)) and turpentine-treated mice. Similarly, IL-6-treated mice displayed a 70% reduction in protein expression and a 40-70% reduction in the mRNA levels of all PGP mdr isoforms. Administration IL-1beta caused an increase in both mdr1b mRNA and protein expression, however, mRNA levels of mdr1a, mdr2 and spgp were significantly reduced. Administration of TNF-alpha also caused increases in mdr1b mRNA. These findings indicate that IL-6 plays a principal role in the downregulation of PGP that is observed in the livers of mice during an inflammatory response.
Hartmann
G
G
Faculty of Pharmacy, University of Toronto, Ontario, Canada.
Kim
H
H
Piquette-Miller
M
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000818:Animals; D016207:Cytokines / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects*; D007375:Interleukin-1 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D012333:RNA, Messenger / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D016207:Cytokines; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha