TY - JOUR
T1 - Interleukin-1β-mediated suppression of RXR:RAR transactivation of the Ntcp promoter is JNK-dependent
AU - Li, Duo
AU - Zimmerman, Tracy L.
AU - Thevananther, Sundararajah
AU - Lee, Ho Young
AU - Kurie, Jonathan M.
AU - Karpen, Saul J.
PY - 2002/8/30
Y1 - 2002/8/30
N2 - Bile flow is rapidly and markedly reduced in hepatic inflammation, correlating with suppression of critical hepatic bile acid transporter gene expression including the principal hepatic bile acid importer, the Na+/taurocholate cotransporting polypeptide (Ntcp, SlclOal). Endotoxin treatment of rats and interleukin-1β (IL-β) treatment of liver-derived HepG2 cells leads to a marked decline in the nuclear binding activity of a main Ntcp gene regulator, the nuclear receptor heterodimer retinoid X receptor:retinoic acid receptor (RXR:RAR). How IL-lβ signaling leads to reduced RXR:RAR nuclear binding activity is unknown, and we sought to determine whether mitogen-activated protein kinase (MAPK) pathways were involved. IL-Iβ treatment of cultured primary rat hepatocytes markedly reduced Ntcp RNA levels and Ntcp promoter activity in transiently transfected HepG2 cells. Pretreatment with inhibitors of extracellular signal-regulated kinase (ERK, PD98059) orp38 MAPK (SB203580) did not affect IL- lβmediated suppression of Ntcp gene expression, whereas curcumin, a derivative of the spice turmeric and a recently described inhibitor of c-Jun N-terminal kinase (JNK), completely ameliorated the effects of IL.lβ. Co-transfection of a JNK expression plasmid inhibited RXR:RAR-mediated activation of the Ntcp promoter, while a dominant negative JNK expression plasmid completely blocked IL-lβ-mediated suppression. Curcumin, but not PD98059 or SB203580, inhibited IL-lβ-mediated suppression of nuclear RXR:RAR binding activity, which correlated with inhibition of JNK phosphorylation and phospho-JNK-mediated phosphorylation of RXR. Taken together, these data provide evidence supporting a novel player (JNK), as well as its inhibitor (curcumin), in inflammation-mediated regulation of hepatobiliary transporters and correlate JNK-dependent RXR phosphorylation with reduced RXR-dependent hepatic gene expression.
AB - Bile flow is rapidly and markedly reduced in hepatic inflammation, correlating with suppression of critical hepatic bile acid transporter gene expression including the principal hepatic bile acid importer, the Na+/taurocholate cotransporting polypeptide (Ntcp, SlclOal). Endotoxin treatment of rats and interleukin-1β (IL-β) treatment of liver-derived HepG2 cells leads to a marked decline in the nuclear binding activity of a main Ntcp gene regulator, the nuclear receptor heterodimer retinoid X receptor:retinoic acid receptor (RXR:RAR). How IL-lβ signaling leads to reduced RXR:RAR nuclear binding activity is unknown, and we sought to determine whether mitogen-activated protein kinase (MAPK) pathways were involved. IL-Iβ treatment of cultured primary rat hepatocytes markedly reduced Ntcp RNA levels and Ntcp promoter activity in transiently transfected HepG2 cells. Pretreatment with inhibitors of extracellular signal-regulated kinase (ERK, PD98059) orp38 MAPK (SB203580) did not affect IL- lβmediated suppression of Ntcp gene expression, whereas curcumin, a derivative of the spice turmeric and a recently described inhibitor of c-Jun N-terminal kinase (JNK), completely ameliorated the effects of IL.lβ. Co-transfection of a JNK expression plasmid inhibited RXR:RAR-mediated activation of the Ntcp promoter, while a dominant negative JNK expression plasmid completely blocked IL-lβ-mediated suppression. Curcumin, but not PD98059 or SB203580, inhibited IL-lβ-mediated suppression of nuclear RXR:RAR binding activity, which correlated with inhibition of JNK phosphorylation and phospho-JNK-mediated phosphorylation of RXR. Taken together, these data provide evidence supporting a novel player (JNK), as well as its inhibitor (curcumin), in inflammation-mediated regulation of hepatobiliary transporters and correlate JNK-dependent RXR phosphorylation with reduced RXR-dependent hepatic gene expression.
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U2 - 10.1074/jbc.M204818200
DO - 10.1074/jbc.M204818200
M3 - Article
C2 - 12105223
AN - SCOPUS:0037200089
SN - 0021-9258
VL - 277
SP - 31416
EP - 31422
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 35
ER -