Faculty Collaboration Database

Identification of interferon-γ as a new molecular target of liver X receptor. Biochem J 2014 Apr 15;459(2):345-54

Date

01/21/2014

Pubmed ID

24438183

DOI

10.1042/BJ20131442

Scopus ID

2-s2.0-84897490281 (requires institutional sign-in at Scopus site)   32 Citations

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.

Author List

Wang Q, Ma X, Chen Y, Zhang L, Jiang M, Li X, Xiang R, Miao R, Hajjar DP, Duan Y, Han J

MESH terms used to index this publication - Major topics in bold

Animals
Cell Line
Female
Gene Expression Regulation
Humans
Hydrocarbons, Fluorinated
Interferon-gamma
Liver X Receptors
Macrophages
Mice
Mice, Inbred C57BL
Mice, Knockout
Neoplasms, Experimental
Orphan Nuclear Receptors
Random Allocation
Sulfonamides