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

Tue Kruse Rasmussen,Christian Møller Sørensen,Kristian Stengaard-Pedersen,Jacob Giehm Mikkelsen,Thomas Andersen,Paul Joseph Utz,Gloria Yiu,Rasmus Otkjær Bak,Christian Kanstrup Holm,Bent Deleuran

doi:10.1186/s13075-015-0660-z

Tue Kruse Rasmussen, Christian Møller Sørensen + Show 8 more

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https://doi.org/10.1186/s13075-015-0660-z

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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.

Highlights

Interleukin (IL)-21 is a key cytokine in autoimmune diseases such as systemic lupus erythematosus (SLE) by its regulation of autoantibody production and inflammatory responses
Basal IL-21 production is increased in memory CD4+ T cells from SLE patients and provides possible feedback for IL-21 induction via STAT3 As IL-21 is implicated in SLE pathogenesis, we examined the main source of IL-21 in SLE
We have demonstrated that STAT3 signaling is decreased in SLE patients compared to Healthy control (HC) and we speculated that miR-155 could in part be responsible for this effect

Summary

Introduction

Interleukin (IL)-21 is a key cytokine in autoimmune diseases such as systemic lupus erythematosus (SLE) by its regulation of autoantibody production and inflammatory responses. Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by inflammation in multiple organ systems [1]. A hallmark of SLE is the production of autoreactive antibodies directed at a conserved group of nuclear antigens [2, 3]. The cause of this loss of tolerance is not well described but presumably involves dysregulated cytokine signaling in T and B cells. In conditions where Tfh cells and IL-21 are increased, elevated autoantibodies and IgG levels are observed in mice and humans [9,10,11,12,13]

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