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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-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.

journal_name

Int Immunopharmacol

journal_title

International immunopharmacology

authors

Hartmann G,Kim H,Piquette-Miller M

doi

10.1016/s0162-3109(00)00271-x

keywords:

subject

Has Abstract

pub_date

2001-02-01 00:00:00

pages

189-99

issue

2

eissn

1567-5769

issn

1878-1705

pii

S0162-3109(00)00271-X

journal_volume

1

pub_type

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