Identification of interferon-{gamma} as a new molecular target of liver X receptor

In this 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 or/and LXRβ expression by siRNA reduced IFN-γ expression. The promoter analysis defined the multiple LXR responsive elements (LXREs) in the proximal region of the IFN-γ promoter. EMSA and ChIP assays 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 node. Functionally, we observed that administration of T0901317 to wild type mice increased rates of survival and being tumor free with inhibited tumor growth when the animals were inoculated with LLC1 carcinoma. In contrast, those 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 tumor growth. Taken together, our study shows that IFN-γ is another molecular target of LXR activation, and it suggests a new mechanism by which LXR inhibits tumor growth.

Source: BJ Cell - January 20, 2014 Category: Biochemistry Authors: Q Wang, X Ma, Y Chen, L Zhang, M Jiang, X Li, R Xiang, R Miao, D P. Hajjar, Y Duan, J Han Tags: BJ Cell Source Type: research