Down-regulation of miR-200a-3p, targeting C-terminal binding protein-2 (CtBP2), is involved in hypoproduction of IL-2 in SLE-derived T cells

ABSTRACT: Systemic lupus erythematosus (SLE) damages multiple organs by producing various autoantibodies. Insufficient interleukin-2 (IL-2) production causes decreased regulatory T cells and permits expansion of autoreactive T cells in the development of SLE. We here show that decreased miR-200a-3p causes IL-2 hypoproduction through directly recruiting ZEB1 or ZEB2 and CtBP2 (ZEB1/ZEB2-CtBP2) complex in SLE T cells. First, we performed RNA sequencing with Illumina Hiseq to obtain the candidate miRNAs and mRNAs involved in the pathogenesis of SLE. We found that miR-200a-3p was significantly downregulated, while its putative targets, ZEB2 and CtBP2 were upregulated in CD4+ T cells in MRL/lpr lupus model mice compared with those of C57BL/6J control mice. ZEB1 and ZEB2 compose ZEB family and suppress various genes including IL-2 by recruiting CtBP2. IL-2 plays a critical role in immune tolerance and IL-2 defect has been recognized in SLE pathogenesis. Therefore, we hypothesized that decreased miR-200a-3p cause IL-2 defect through ZEB1/ZEB2-CtBP2 complex in SLE CD4+T cells. Overexpression of miR-200a-3p induced IL-2 production though downregulating ZEB1, ZEB2 and CtBP2 in EL4 cell lines. We further revealed that miR-200a-3p promote IL-2 expression by reducing the bindings of suppressive ZEB1/ZEB2-CtBP2 complex on NRE-A of IL-2 promoter in SLE murine T cells. Interestingly, ZEB1/ZEB2-CtBP2 complex on NRE-A (a negative regulatory element) were significantly upregulated after phorbol-12-myristate-13-acetate and ionomycin (PMA/Iono) stimulation in lupus T cells. Our findings provide a new insight for the epigenetic regulation of IL-2 defect in SLE.

ORGANISM(S): Mus musculus

PROVIDER: GSE87219 | GEO | 2016/09/23

SECONDARY ACCESSION(S): PRJNA343928

REPOSITORIES: GEO