Redundant roles for cJun-N-terminal kinase 1 and 2 in interleukin-1β-mediated reduction and modification of murine hepatic nuclear retinoid X receptor α

JOURNAL OF HEPATOLOGY

卷:51

Article

Kosters, Astrid¹  White, Damara D.¹  Sun, Hongdan¹  Thevananther, Sundararajah¹  Karpen, Saul J.¹ 

[1] Baylor Coll Med, Dept Pediat, Texas Childrens Liver Ctr, Houston, TX 77030 USA

关键词: Liver;    RXR alpha;    JNK;    IL-1 beta;    Inflammation;   

DOI  :  10.1016/j.jhep.2009.06.029

来源: Elsevier

【 摘 要 】

Background/Aims: Retinoid X receptor alpha (RXR alpha), the heterodimeric partner for multiple nuclear receptors (NRs), was shown to be an essential target for inflammation-induced cJun-N-terminal kinase (JNK) signaling in vitro. This study aimed to explore the role of hepatic JNK signaling and its effects on nuclear RXR alpha levels downstream of interieukin-1 beta (IL-1 beta) in vivo. Methods: Effects of IL-1 beta on hepatic NR-dependent gene expression, nuclear RXR alpha levels, and roles for individual JNK isoforms were studied in wild-type, Jnk1(-/-), and Jnk2(-/-) mice and in primary hepatocytes of each genotype. Results: IL-1 beta administration showed a time-dependent reduction in expression of the hepatic NR-dependent genes Ntep, Cyp7a1, Cyp8b1, Abcg5, Mrp2, and Mrp3. IL-1 beta treatment for 1 h activated JNK and resulted in both post-translational modification and reduction of nuclear RXR alpha. In wild-type primary hepatocytes, IL-1 beta modified and reduced nuclear RXR alpha levels time dependently, which was prevented by chemical inhibition of JNK as well as by inhibition of proteasomal degradation. Individual absence of either JNK1 or JNK2 did not significantly influence the reduction or modification of hepatic nuclear RXR alpha by IL-1 beta both in vivo and in primary hepatocytes. Conclusions: Functional redundancy exists for JNK1 and JNK2 in IL-1 beta-mediated alterations of hepatic nuclear RXR alpha levels, stressing the importance of this pathway in mediating the hepatic response to inflammation. (C) 2009 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

【 授权许可】

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