Decreased expression of P-glycoprotein in interleukin-1beta and interleukin-6 treated rat hepatocytes.
OBJECTIVE
As acute inflammation is known to cause a reduction in hepatic P-Glycoprotein (PGP) expression and activity in rats, we tested the hypothesis that the pro-inflammatory cytokines interleukin (IL-)1beta and IL-6 also mediate reductions in PGP.


METHODS
Hepatocytes were incubated with 0-50 ng/ml of cytokine for 24-72 h. PGP/mdr expression was examined by immunodetection and quantitative RT-PCR analysis and PGP efflux activity was assayed.


RESULTS
PGP protein was significantly reduced in cells treated for 3 days with IL-1beta and 24 h with IL-6 (p < 0.05), maximal effects occurring at 5 ng/ml for each cytokine. PGP activity was reduced in both IL-1beta and IL-6 treated cells (p < 0.05). mdr1 mRNA was decreased in cells treated with IL-6, but not IL-1beta. spgp and mdr2 were not affected.


CONCLUSIONS
Our data indicate that IL-6 and IL-1beta have suppressive effects on the expression and activity of PGP in cultured hepatocytes, likely occurring through distinct mechanisms. These cytokines may have a potential role in PGP regulation during inflammatory responses.
Sukhai
M
M
Faculty of Pharmacy, University of Toronto, Ontario, Canada.
Yong
A
A
Pak
A
A
Piquette-Miller
M
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis*; D000818:Animals; D015153:Blotting, Western; D002469:Cell Separation; D002478:Cells, Cultured; D004396:Coloring Agents; D003907:Dexamethasone / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D019450:Genes, MDR / Q000235:genetics; D005938:Glucocorticoids / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D007375:Interleukin-1 / Q000494:pharmacology*; D015850:Interleukin-6 / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020112:Rhodamine 123
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004396:Coloring Agents; D005938:Glucocorticoids; D007375:Interleukin-1; D015850:Interleukin-6; D012333:RNA, Messenger; D020112:Rhodamine 123; D003907:Dexamethasone