Lashine Y A, Salah S, Aboelenein H R, Abdelaziz A I
The Molecular Pathology Research Group, the German University in Cairo, Cairo, Egypt.
Abou el Reesh Pediatric Hospital, Kasr Al Aini, Cairo University, Cairo, Egypt.
Lupus. 2015 Mar;24(3):240-7. doi: 10.1177/0961203314552117. Epub 2014 Sep 24.
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.
微小RNA-155参与免疫细胞的分化、成熟及功能。在系统性红斑狼疮（SLE）和类风湿关节炎（RA）等自身免疫性疾病患者中，miR-155呈现出表达失调的变化。此前已证实miR-155直接靶向环磷酸腺苷反应元件结合蛋白（CREB），而CREB此前被鉴定为蛋白磷酸酶2A（PP2A）的正向调节因子。PP2A是白细胞介素-2的关键负向调节因子，白细胞介素-2是一种重要的免疫调节剂，此前研究表明其在SLE中水平降低。在本研究中，我们旨在探究miR-155对PP2A的调控作用及其在青少年SLE疾病发病机制中的作用。miR-155在青少年SLE和青少年家族性地中海热（FMF）患者的外周血单个核细胞（PBMC）中显著下调，而在青少年特发性关节炎（JIA）患者的PBMC中显著上调。在SLE中，miR-155的表达与系统性红斑狼疮疾病活动指数（SLEDAI）评分及蛋白尿呈负相关，与白细胞（WBC）计数呈正相关。PP2A催化亚基（PP2Ac）的mRNA在SLE和FMF患者的PBMC中显著上调，但在JIA患者中未上调。此外，PP2Ac mRNA的相对表达与SLEDAI评分呈正相关。在培养刺激的PBMC中，强制表达miR-155导致PP2Ac mRNA的相对表达降低，白细胞介素-2释放增加。本研究首次提示miR-155-PP2Ac环路在调节白细胞介素-2释放中的可能作用，并通过解除PP2A对白细胞介素-2的抑制作用，将miR-155鉴定为青少年SLE疾病的潜在治疗靶点。
