Increased HERV-E clone 4-1 expression contributes to DNA hypomethylation and IL-17 release from CD4⁺ T cells via miR-302d/MBD2 in systemic lupus erythematosus.

BACKGROUND:Increased human endogenous retroviruses E clone 4-1 (HERV-E clone 4-1) mRNA expression is observed in systemic lupus erythematosus (SLE) patients and associates with the disease activity. In this study, we want to further investigate the mechanism of HERV-E clone 4-1 mRNA upregulation and its roles in SLE progression. METHODS:CD4⁺ T cells were isolated from venous blood of SLE patients or healthy controls and qRT-PCR was used to detect HERV-E clone 4-1 mRNA expression. We then investigated the regulation of Nuclear factor of activated T cells 1 (NFAT1) and Estrogen receptor-α (ER-α) on HERV-E clone 4-1 transcription and the functions of HERV-E clone 4-1 3' long terminal repeat (LTR) on DNA hypomethylation and IL-17 release. RESULTS:We found HERV-E clone 4-1 mRNA expression was upregulated in CD4⁺ T cells from SLE patients and positively correlated with SLE disease activity. This is associated with the activation of Ca²⁺/calcineurin (CaN)/NFAT1 and E2/ER-α signaling pathway and DNA hypomethylation of HERV-E clone 4-1 5'LTR. HERV-E clone 4-1 also takes part in disease pathogenesis of SLE through miR-302d/Methyl-CpG binding domain protein 2 (MBD2)/DNA hypomethylation and IL-17 signaling via its 3'LTR. CONCLUSIONS:HERV-E clone 4-1 mRNA upregulation is due to the abnormal inflammation/immune/methylation status of SLE and it could act as a potential biomarker for diagnosis of SLE. HERV-E clone 4-1 also takes part in disease pathogenesis of SLE via its 3'LTR and the signaling pathways it involved in may be potential therapeutic targets of SLE.

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