LXR (liver X receptor) is a ligand-activated transcription factor and plays an important role in regulation of lipid homoeostasis and inflammation. Several studies indicate that LXR inhibits IFN-γ (interferon γ)-induced biological responses; however, the influence of LXR on IFN-γ expression has not been fully elucidated. In the present study, we investigated the effects of LXR activation on IFN-γ expression at different levels. At the molecular level, we surprisingly observed that LXR ligand (T0901317) induced macrophage and T-cell IFN-γ protein expression which was associated with increased mRNA and secreted protein levels in culture medium. In contrast, selective inhibition of LXRα and/or LXRβ expression by siRNA reduced IFN-γ expression. Promoter analysis defined the multiple LXREs (LXR-responsive elements) in the proximal region of the IFN-γ promoter. EMSAs and ChIP indicated that LXR activation enhanced the binding of LXR protein to these LXREs. In vivo, T0901317 increased wild-type mouse serum IFN-γ levels and IFN-γ expression in the lung and lymph nodes. Functionally, we observed that administration of T0901317 to wild-type mice increased rates of survival and being tumour-free, and inhibited tumour growth when the animals were inoculated with LLC1 carcinoma. In contrast, these protective effects were substantially attenuated in IFN-γ-knockout (IFN-γ−/−) mice, suggesting that the induction of IFN-γ production plays a critical role in T0901317-inhibited tumour growth. Taken together, the results of the present study show that IFN-γ is another molecular target of LXR activation, and it suggests a new mechanism by which LXR inhibits tumour growth.
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Research Article|
March 28 2014
Identification of interferon-γ as a new molecular target of liver X receptor Available to Purchase
Qixue Wang;
Qixue Wang
*State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, China
†College of Life Sciences, Nankai University, Tianjin 300071, China
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Xingzhe Ma;
Xingzhe Ma
*State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, China
†College of Life Sciences, Nankai University, Tianjin 300071, China
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Yuanli Chen;
Yuanli Chen
†College of Life Sciences, Nankai University, Tianjin 300071, China
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Ling Zhang;
Ling Zhang
†College of Life Sciences, Nankai University, Tianjin 300071, China
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Meixiu Jiang;
Meixiu Jiang
†College of Life Sciences, Nankai University, Tianjin 300071, China
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Xiaoju Li;
Xiaoju Li
†College of Life Sciences, Nankai University, Tianjin 300071, China
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Rong Xiang;
Rong Xiang
‡Collaborative Innovation Center of Biotherapy, Nankai University, Tianjin 300071, China
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Robert Miao;
Robert Miao
§Medical College of Wisconsin, Milwaukee, WI 53213, U.S.A.
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David P. Hajjar;
David P. Hajjar
∥Weill Cornell Medical College, New York, NY 10065, U.S.A.
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Yajun Duan;
Yajun Duan
1
*State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, China
‡Collaborative Innovation Center of Biotherapy, Nankai University, Tianjin 300071, China
1Correspondence may be addressed to either of these authors (email [email protected] or [email protected]).
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Jihong Han
Jihong Han
1
*State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, China
†College of Life Sciences, Nankai University, Tianjin 300071, China
‡Collaborative Innovation Center of Biotherapy, Nankai University, Tianjin 300071, China
1Correspondence may be addressed to either of these authors (email [email protected] or [email protected]).
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Publisher: Portland Press Ltd
Received:
November 01 2013
Revision Received:
January 02 2014
Accepted:
January 20 2014
Accepted Manuscript online:
January 20 2014
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2014 Biochemical Society
2014
Biochem J (2014) 459 (2): 345–354.
Article history
Received:
November 01 2013
Revision Received:
January 02 2014
Accepted:
January 20 2014
Accepted Manuscript online:
January 20 2014
Connected Content
A commentary has been published:
Liver X receptor: from metabolism to cancer
Citation
Qixue Wang, Xingzhe Ma, Yuanli Chen, Ling Zhang, Meixiu Jiang, Xiaoju Li, Rong Xiang, Robert Miao, David P. Hajjar, Yajun Duan, Jihong Han; Identification of interferon-γ as a new molecular target of liver X receptor. Biochem J 15 April 2014; 459 (2): 345–354. doi: https://doi.org/10.1042/BJ20131442
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