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 TNFalpha, interferon-gamma, interleukin-6, and interleukin-1 activate the ERVWE1 promoter, while the MS-protective interferon-beta 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 TNFalpha had the ability to activate the ERVWE1 promoter through an NF-kappaB-responsive element located within the enhancer domain of the promoter. Electrophoretic mobility shift and ChIP assays showed that TNFalpha enhances the binding of the p65 subunit of NF-kappaB, to its cognate site within the promoter. The effect of TNFalpha is abolished by siRNA directed against p65. Taken together, these results illustrate a role for p65 in regulating the ERVWE1 promoter and in TNFalpha-mediated induction of syncytin-1 in multiple sclerosis.
Mameli
Giuseppe
G
Section of Microbiology, Department of Biomedical Sciences, Center of Excellence for Biotechnology Development and Biodiversity Research, Sassari, Italy. viross@uniss.it
Astone
Vito
V
Khalili
Kamel
K
Serra
Caterina
C
Sawaya
Bassel E
BE
Dolei
Antonina
A
D001253:Astrocytes / Q000378:metabolism*; D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D005786:Gene Expression Regulation; D015686:Gene Products, env / Q000235:genetics*; D017930:Genes, Reporter; D006801:Humans; D008156:Luciferases / Q000032:analysis / Q000235:genetics; D009103:Multiple Sclerosis / Q000276:immunology*; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D011257:Pregnancy Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D034622:RNA Interference; D017384:Sequence Deletion; D051996:Transcription Factor RelA / Q000378:metabolism
D016207:Cytokines; D015686:Gene Products, env; D052002:NF-kappa B p50 Subunit; D011257:Pregnancy Proteins; D051996:Transcription Factor RelA; C405335:syncytin; D008156:Luciferases