Identification of interferon-γ as a new molecular target of liver X receptor
Qixue Wang, Xingzhe Ma, Yuanli Chen1
1†College of Life Sciences, Nankai University, Tianjin 300071, China.
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.
Insights
Liver X receptor (LXR) activation surprisingly induces interferon-gamma (IFN-γ) production, enhancing anti-tumor responses. This study reveals IFN-γ as a novel LXR target, clarifying LXR
Area of Science:
- Immunology and Molecular Biology
- Cancer Research
- Metabolic Regulation
Background:
- Liver X receptor (LXR) is a key regulator of lipid homeostasis and inflammation.
- Previous research suggested LXR inhibits interferon-gamma (IFN-γ) activity, but its effect on IFN-γ expression was unclear.
Purpose of the Study:
- To investigate the impact of LXR activation on IFN-γ expression at molecular and in vivo levels.
- To determine the role of LXR-induced IFN-γ in LXR's anti-tumor effects.
Main Methods:
- Treated macrophages and T-cells with LXR ligand (T0901317) and assessed IFN-γ mRNA and protein.
- Utilized siRNA to inhibit LXRα/LXRβ expression and analyzed IFN-γ levels.
- Performed promoter analysis, Electrophoretic Mobility Shift Assays (EMSAs), and Chromatin Immunoprecipitation (ChIP) to study LXR binding to the IFN-γ promoter.
- Administered T0901317 to wild-type and IFN-γ-knockout mice, measuring serum IFN-γ and evaluating tumor growth and survival.
Main Results:
- LXR ligand T0901317 unexpectedly increased IFN-γ protein and mRNA expression in macrophages and T-cells.
- Inhibition of LXRα/LXRβ reduced IFN-γ expression, confirming LXR's role in its induction.
- LXR activation enhanced LXR binding to specific elements (LXREs) in the IFN-γ promoter.
- In vivo, T0901317 boosted serum and tissue IFN-γ levels in wild-type mice.
- T0901317 administration inhibited tumor growth and improved survival in wild-type mice, an effect diminished in IFN-γ-knockout mice.
Conclusions:
- Interferon-gamma (IFN-γ) is identified as a novel molecular target of Liver X receptor (LXR) activation.
- LXR activation promotes IFN-γ production, contributing to its observed anti-tumorigenic effects.
- This study elucidates a new mechanism for LXR-mediated tumor inhibition via IFN-γ induction.
