Overexpression of microRNA-155 increases IL-21 mediated STAT3 signaling and IL-21 production in systemic lupus erythematosus

Abstract

IntroductionInterleukin (IL)-21 is a key cytokine in autoimmune diseases such as systemic lupus erythematosus (SLE) by its regulation of autoantibody production and inflammatory responses. The objective of this study is to investigate the signaling capacity of IL-21 in T and B cells and assess its possible regulation by microRNA (miR)-155 and its target gene suppressor of cytokine signaling 1 (SOCS1) in SLE.MethodsThe signaling capacity of IL-21 was quantified by stimulating peripheral blood mononuclear cells (PBMCs) with IL-21 and measuring phosphorylation of STAT3 (pSTAT3) in CD4+ T cells, B cells, and natural killer cells. Induction of miR-155 by IL-21 was investigated by stimulating purified CD4+ T cells with IL-21 and measuring miR-155 expression levels. The functional role of miR-155 was assessed by overexpressing miR-155 in PBMCs from SLE patients and healthy controls (HCs) and measuring its effects on STAT3 and IL-21 production in CD4+ and CD8+ T cells.ResultsInduction of pSTAT3 in CD4+ T cells in response to IL-21 was significantly decreased in SLE patients compared to HCs (p < 0.0001). Further, expression levels of miR-155 were significantly decreased and SOCS1 correspondingly increased in CD4+ T cells from SLE patients. Finally, overexpression of miR-155 in CD4+ T cells increased STAT3 phosphorylation in response to IL-21 treatment (p < 0.01) and differentially increased IL-21 production in SLE patients compared to HCs (p < 0.01).ConclusionWe demonstrate that SLE patients have reduced IL-21 signaling capacity, decreased miR-155 levels, and increased SOCS1 levels compared to HCs. The reduced IL-21 signaling in SLE could be rescued by overexpression of miR-155, suggesting an important role for miR-155 in the reduced IL-21 signaling observed in SLE.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-015-0660-z) contains supplementary material, which is available to authorized users.

Schizandrin A Alleviates LPS-Induced Injury in Human Keratinocyte Cell Hacat Through a MicroRNA-127-Dependent Regulation

“…Meanwhile, miRNAs were also found to be novel regulators in skin inflammation [2]. Numerous reports illustrated the role of miRNAs in skin inflammation response and cytokine signaling pathways, such as miR-155 [13], miR-1246 [14], miR-145 and miR-224 [15]. Among all these identified miRNAs, abnormal expression of miR-127 was reported to be link to inflammatory disorders [16].…”

MiR-410 Down-Regulates the Expression of Interleukin-10 by Targeting STAT3 in the Pathogenesis of Systemic Lupus Erythematosus

“…In SLE, the phosphorylation of STAT3 forms a homodimer, which translocates to the nucleus where it initiates transcription of target genes including the IL-10, IL-17A and IL-21. This forms an autocrine loop for their production via STAT3 phosphorylation [22,43]. Thus, we can conclude that miRNA-410 regulated the inactivation of STAT3 by suppressing the phosphorylation as well as the expression level of STAT3 via directly targeting STAT3 gene in CD3+ T cells of SLE patients.…”

“…STAT3 is a critical member of the STAT transcription factor family. It is reported that overexpression of miR-155 in CD4+ T cells increased STAT3 phosphorylation in response to IL-21 treatment in SLE [22]. Also, Hedrich et al reported that in lupus T cells, the increasing level of IL-10 was promoted by STAT3 [43].…”

“…Over-expression of miR-155 significantly increased IL-21 mediated STAT signaling in SLE [22,25]. In order to find whether STAT3 is the target of miR-410, luciferase reporter assay was performed.…”

“…1A). As we have known, in the subsets of T cells, CD4+ T cells which are important immune cells in the immune system, have been also used to study the microRNA regulation in SLE [22,23]. Also, the miRNA-410 level was tested in CD4+ T cells (Fig.…”