Inflammation and interleukin-6 mediate reductions in the hepatic expression and transcription of the mdr1a and mdr1b Genes.
In order to elucidate the mechanisms involved in the downregulation of mdr 1 gene expression reported in experimentally-induced inflammation, we examined the effects of experimentally-induced inflammation and interleukin-(IL-) 6 on transcriptional control of the mdr1 genes in rats. RNA, nuclear extracts, and nuclear protein fractions were isolated from livers harvested from saline or turpentine-treated male Sprague-Dawley rats or from IL-6 treated or nontreated (controls) cultured rat hepatocytes. mdr gene expression and regulation was examined by RT-PCR, mRNA stability studies, nuclear run-on analysis of transcription, and gel shift analysis of promoter-transcription factor interaction. As compared to controls, significantly lower levels of mdr1a and mdr1b mRNA and significantly decreased mdr1a and mdr1b transcription rates were observed in livers isolated from the turpentine-treated rats. In vitro treatments of cultured hepatocytes with IL-6 also suppressed mdr1a and mdr1b mRNA expression and imposed similar reductions in mdr1a and mdr1b transcriptional activity. Significant effects of IL-6 on mdr1 mRNA stability were not seen. Our results indicate that reductions in mdr1 expression in experimental models of inflammation likely occurs through altered gene transcription. Furthermore, as IL-6 was found to decrease mdr1 expression and gene transcription rates in vitro, this cytokine is likely involved in the reduction of mdr1 expression that is seen in vivo during an acute inflammatory response.
Sukhai
M
M
Faculty of Pharmacy, University of Toronto, 19 Russell Street, Toronto, Ontario, Canada.
Yong
A
A
Kalitsky
J
J
Piquette-Miller
M
M
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism*; D015850:Interleukin-6 / Q000494:pharmacology*; D008099:Liver / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D008297:Male; D011401:Promoter Regions, Genetic / Q000502:physiology; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014425:Turpentine; D000097202:ATP-Binding Cassette Sub-Family B Member 4
D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; D015850:Interleukin-6; D012333:RNA, Messenger; D014157:Transcription Factors; D014425:Turpentine; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C095122:multidrug resistance protein 3