Regulation of the hepatic multidrug resistance gene expression by endotoxin and inflammatory cytokines in mice

Abstract

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-1β and tumor necrosis factor (TNF)-α) 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-1β caused an increase in both mdr1b mRNA and protein expression, however, mRNA levels of mdr1a, mdr2 and spgp were significantly reduced. Administration of TNF-α 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.