Interleukin-1 beta-mediated suppression of RXR:RAR transactivation of the Ntcp promoter is JNK-dependent.
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 co-transporting polypeptide (Ntcp, Slc10a1). Endotoxin treatment of rats and interleukin-1 beta (IL-1 beta) 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-1 beta 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-1 beta 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) or p38 MAPK (SB203580) did not affect IL-1 beta-mediated 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-1 beta. 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-1 beta-mediated suppression. Curcumin, but not PD98059 or SB203580, inhibited IL-1 beta-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.
Li
Duo
D
Texas Children's Liver Center, Department of Pediatrics/GI & Nutrition, Baylor College of Medicine, Houston, Texas 77030, USA.
Zimmerman
Tracy L
TL
Thevananther
Sundararajah
S
Lee
Ho-Young
HY
Kurie
Jonathan M
JM
Karpen
Saul J
SJ
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D005982:Glutathione Transferase / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008114:Liver Neoplasms, Experimental; D008297:Male; D026901:Membrane Transport Proteins; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D029363:Organic Anion Transporters, Sodium-Dependent; D011401:Promoter Regions, Genetic; D051381:Rats; D017207:Rats, Sprague-Dawley; D018168:Receptors, Retinoic Acid / Q000187:drug effects / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D047488:Retinoid X Receptors; D027981:Symporters; D014157:Transcription Factors / Q000187:drug effects / Q000502:physiology*; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured
D002352:Carrier Proteins; D007375:Interleukin-1; D026901:Membrane Transport Proteins; D029363:Organic Anion Transporters, Sodium-Dependent; D018168:Receptors, Retinoic Acid; D011993:Recombinant Fusion Proteins; D047488:Retinoid X Receptors; D027981:Symporters; D014157:Transcription Factors; C071908:sodium-bile acid cotransporter; D005982:Glutathione Transferase; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases