Regulation of the syncytin-1 promoter in human astrocytes by multiple sclerosis-related cytokines

Syncytin-1 has a physiological role during early pregnancy, as mediator of trophoblast fusion into the syncytiotrophoblast layer, hence
allowing embryo implantation. In addition, its expression in nerve tissue has been proposed to contribute to the pathogenesis of multiple sclerosis
(MS). Syncytin-1 is the env glycoprotein of the ERVWE1 component of the W family of human endogenous retroviruses (HERV), located on
chromosome 7q21–22, in a candidate region for genetic susceptibility to MS. The mechanisms of ERVWE1 regulation in nerve tissue remain to
be identified. Since there are correlations between some cytokines and MS outcome, we examined the regulation of the syncytin-1 promoter by
MS-related cytokines in human U-87MG astrocytic cells. Using transient transfection assays, we observed that the MS-detrimental cytokines
TNFα, interferon-γ, interleukin-6, and interleukin-1 activate the ERVWE1 promoter, while the MS-protective interferon-β is inhibitory. The
effects of cytokines are reduced by the deletion of the cellular enhancer domain of the promoter that contains binding sites for several transcription
factors. In particular, we found that TNFα had the ability to activate the ERVWE1 promoter through an NF-κB-responsive element located within
the enhancer domain of the promoter. Electrophoretic mobility shift and ChIP assays showed that TNFα enhances the binding of the p65 subunit
of NF-κB, to its cognate site within the promoter. The effect of TNFα is abolished by siRNA directed against p65. Taken together, these results
illustrate a role for p65 in regulating the