Identification of interferon-γ as a new molecular target of liver X receptor.
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.
Qixue
Q
Wang
Xingzhe
X
Ma
†College of Life Sciences, Nankai University, Tianjin 300071, China.
Yuanli
Y
Chen
†College of Life Sciences, Nankai University, Tianjin 300071, China.
Ling
L
Zhang
†College of Life Sciences, Nankai University, Tianjin 300071, China.
Meixiu
M
Jiang
†College of Life Sciences, Nankai University, Tianjin 300071, China.
Xiaoju
X
Li
‡Collaborative Innovation Center of Biotherapy, Nankai University, Tianjin 300071, China.
Rong
R
Xiang
§Medical College of Wisconsin, Milwaukee, WI 53213, U.S.A.
Robert
R
Miao
∥Weill Cornell Medical College, New York, NY 10065, U.S.A.
David P
DP
Hajjar
Yajun
Y
Duan
Jihong
J
Han
D000818:Animals; D002460:Cell Line; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism*; D000071518:Liver X Receptors; D008264:Macrophages; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009374:Neoplasms, Experimental; D057093:Orphan Nuclear Receptors / Q000235:genetics / Q000378:metabolism*; D011897:Random Allocation; D013449:Sulfonamides / Q000494:pharmacology; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D006845:Hydrocarbons, Fluorinated; D007371:Interferon-gamma; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D013449:Sulfonamides; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides