MicroRNA-155 is involved in immune cell, differentiation, maturation and function. MiR-155 showed variable dysregulated expression in autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) patients. MiR-155 was previously confirmed to directly target CAMP response element binding protein (CREB), which was previously identified as a positive regulator of protein phosphatase 2A (PP2A). PP2A is a key negative regulator of interleukin-2, which is an important immune modulator and was previously shown to be decreased in SLE. In this study we aimed at investigating the regulation of PP2A by miR-155 and hence its role in juvenile SLE disease pathogenesis. MiR-155 showed significant downregulation in PBMCs from juvenile SLE and juvenile familial Mediterranean fever (FMF) and significant upregulation in PBMCs from juvenile idiopathic arthritis (JIA) patients. In SLE, miR-155 expression was negatively correlated with Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score and proteinuria and was positively correlated with white blood cell (WBC) count. The mRNA of the catalytic subunit of PP2A (PP2Ac) showed significant upregulation in PBMCs from SLE and FMF but not in JIA patients. Additionally, the relative expression of PP2Ac mRNA was positively correlated with SLEDAI score. Forced expression of miR-155 led to decreased relative expression of PP2Ac mRNA and increased IL-2 release in cultured-stimulated PBMCs. This study suggests for the first time the possible role of an miR-155-PP2Ac loop in regulating IL-2 release and identifies miR-155 as a potential therapeutic target in juvenile SLE disease through relieving IL-2 from the inhibitory role of PP2A.
microRNA-155 (miR-155) is implicated in regulating B-cell activation and survival that is important in systemic lupus erythematosus (SLE) pathogenesis. PU.1, a target for miR-155, is a crucial regulator of B-cell development and enhances Tumour-Necrosis-factor-alpha (TNF-α) expression. TNF-α induces the expression of B-cell-activating-factor (BAFF). BAFF is reported to increase the expression of the autoimmunity marker; CD19. This study aimed to investigate the regulation of expression of PU.1 in pediatric-systemic-lupus-erythematosus (pSLE) patients by miR-155, and hence evaluate its impact on TNF-α/BAFF/CD19 signalling pathway. Screening revealed that PU.1 is upregulated in PBMCs and B-cells of pSLE patients. PU.1 expression directly correlated with systemic-lupus-erythematosus disease-activity-index-2 K SLEDAI-2K. Ectopic expression of miR-155 and knockdown of PU.1 suppressed PU.1, TNF-α and BAFF. Finally, miR-155 decreased the proportion of BAFF-expressing-B-cells and CD19 protein expression. These findings suggest that miR-155 suppresses autoimmunity through transcriptional repression of PU.1 and TNF-α, which in turn suppresses BAFF and CD19 protein expression.
The altered expression of the triad, miR-27a* as well as NKG2D and ULBP2, is thought to be characteristic for NK cells in SLE patients. Hence, the ability of miR-27a* to alter the expression of NKG2D may provide a new groundwork for understanding the role of miRNAs in NK cells of SLE patients.
The main objective of this study is to investigate the relative expression of miRNA 17-5p and one of its target genes E2F1 in the peripheral blood of systemic lupus erythematosus pediatric patients. The expression of miRNA 17-5p and its target E2F1 mRNA was analyzed by TaqMan real-time qPCR. Our results showed significant downregulation of miRNA 17-5p in SLE patients compared to healthy controls; moreover, miRNA 17-5p was more downregulated in patients on no treatment compared to those on treatment. Relative expression of E2F1, which is a target for miRNA 17-5p, was significantly downregulated as well on both mRNA and protein levels in SLE pediatric patients. In conclusion, our data show an unexpected dual downregulation of both miRNA 17-5p and its target gene E2F1 on the mRNA and protein levels. This may suggest an expression pattern of miRNA 17-5p and its target E2F1 that may be specific to SLE. [corrected].
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