Premium
Interleukin‐1β represses MRP 2 gene expression through inactivation of interferon regulatory factor 3 in HepG2 cells
Author(s) -
Hisaeda Keiji,
Inokuchi Akihiko,
Nakamura Takanori,
Iwamoto Yukihide,
Kohno Kimitoshi,
Kuwano Michihiko,
Uchiumi Takeshi
Publication year - 2004
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.20216
Subject(s) - multidrug resistance associated protein 2 , irf3 , microbiology and biotechnology , biology , irf1 , downregulation and upregulation , electrophoretic mobility shift assay , transfection , interferon , gene expression , transcription factor , biochemistry , immunology , gene , atp binding cassette transporter , transporter
The human multidrug resistance protein 2 ( MRP 2/ABCC2), expressed on the bile canalicular membrane, mediates the multispecific efflux of several organic anions, including conjugates of glucuronate, sulfate, and glutathione. Expression of MRP2 can be altered in response to environmental stimuli such as cholestasis and jaundice. We previously reported that MRP2 mRNA expression levels are decreased in the nontumorous part of hepatitis C virus‐infected human liver tissues, and that inflammatory cytokines inhibit MRP2 expression in human hepatic (HepG2) cells. We investigated the molecular mechanisms by which inflammatory cytokines modulate MRP2 gene expression in hepatic cells. Treatment of human hepatic cells with interleukin‐1β (IL‐1β) or tumor necrosis factor α resulted in a decrease in the protein and mRNA levels of MRP2 . IL‐1β inhibited the transcriptional activity of MRP2 promoter constructs by 40%, and this inhibition of MRP2 promoter activity was mediated through the interferon stimulatory response element (ISRE). Electrophoretic mobility shift assays with IL‐1β‐treated nuclear extracts showed a decrease in the formation of DNA protein complexes, specifically those including interferon regulatory factor 3 (IRF3). Expression of recombinant human IRF3 increased MRP2 promoter activity. Treatment with a specific extracellular signal‐regulated kinase inhibitor relieved IL‐1β‐induced MRP2 mRNA downregulation and abrogated the binding of IRF3 to the ISRE element. In conclusion , IL‐1β induces downregulation of the MRP2 gene by inactivating IRF3 binding to ISRE on the MRP2 promoter in human hepatic cells; this inactivation is accomplished via interference with the extracellular signal‐regulated kinase pathway. (H EPATOLOGY 2004;39:1574–1582.)