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Originally published In Press as doi:10.1074/jbc.M204818200 on June 24, 2002

J. Biol. Chem., Vol. 277, Issue 35, 31416-31422, August 30, 2002
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Interleukin-1beta -mediated Suppression of RXR:RAR Transactivation of the Ntcp Promoter Is JNK-dependent*

Duo LiDagger , Tracy L. ZimmermanDagger , Sundararajah ThevanantherDagger , Ho-Young Lee§, Jonathan M. Kurie§, and Saul J. KarpenDagger ||

From the Dagger  Texas Children's Liver Center, Department of Pediatrics/GI & Nutrition, Baylor College of Medicine, Houston, Texas 77030 and the § Department of Thoracic/Head and Neck Medical Oncology, M. D. Anderson Cancer Center, Houston, Texas 77030

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-1beta (IL-1beta ) 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-1beta 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-1beta 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-1beta -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-1beta . 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-1beta -mediated suppression. Curcumin, but not PD98059 or SB203580, inhibited IL-1beta -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.

* This work was supported by National Institutes of Health Grants DK56239 (to S. J. K.) and CA80686 (to J. M. K.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

A Sidney Kimmel Foundation Scholar.

|| To whom correspondence should be addressed: Texas Children's Liver Center, Dept. of Pediatrics/GI & Nutrition, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030. Tel.: 832-824-3754; Fax: 832-825-4893; E-mail: skarpen@bcm.tmc.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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