Identification of interferon-γ as a new molecular target of liver X receptor.

Abstract

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.

• Authors: Qixue Wang, Xingzhe Ma, Yuanli Chen, Ling Zhang, Meixiu Jiang, Xiaoju Li, Rong Xiang, Robert Miao, David P Hajjar, Yajun Duan, Jihong Han
• Journal: The Biochemical journal (Biochem J) Vol. 459 Issue 2 Pg. 345-54 (Apr 15 2014) ISSN: 1470-8728 [Electronic] England
• PMID: 24438183 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Hydrocarbons, Fluorinated
• Liver X Receptors
• NR1H3 protein, human
• Nr1h3 protein, mouse
• Orphan Nuclear Receptors
• Sulfonamides
• T0901317
• Interferon-gamma

Topics

• Animals
• Cell Line
• Female
• Gene Expression Regulation (drug effects, physiology)
• Humans
• Hydrocarbons, Fluorinated (pharmacology)
• Interferon-gamma (genetics, metabolism)
• Liver X Receptors
• Macrophages
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Neoplasms, Experimental
• Orphan Nuclear Receptors (genetics, metabolism)
• Random Allocation
• Sulfonamides (pharmacology)