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

Int Immunopharmacol. 2001 Feb;1(2):189-99. doi: 10.1016/s0162-3109(00)00271-x.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics*
  • Animals
  • Cytokines / pharmacology*
  • Drug Resistance, Multiple / genetics
  • Gene Expression Regulation / drug effects*
  • Interleukin-1 / pharmacology
  • Interleukin-6 / pharmacology
  • Lipopolysaccharides / pharmacology*
  • Liver / metabolism*
  • Male
  • Mice
  • RNA, Messenger / analysis
  • Tumor Necrosis Factor-alpha / pharmacology


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Cytokines
  • Interleukin-1
  • Interleukin-6
  • Lipopolysaccharides
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha