title: Overexpression of microRNA-155 increases IL-21 mediated STAT3 signaling and IL-21 production in systemic lupus erythematosus.
abstract: BACKGROUND
  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. 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.
  
  
  METHODS
  The 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.
  
  
  RESULTS
  Induction 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).
  
  
  CONCLUSIONS
  We 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.
authors.affiliation: Department of Biomedicine, Aarhus University, 8000, Aarhus C, Denmark. tue.kruse@biomed.au.dk.|Department of Medicine, Division of Immunology and Rheumatology, Stanford School of Medicine, Stanford, CA, USA. tue.kruse@biomed.au.dk.|Department of Rheumatology, Aarhus University Hospital, 8000, Aarhus C, Denmark. tue.kruse@biomed.au.dk.
authors.forename: Tue Kruse
authors.initials: TK
authors.lastname: Rasmussen
authors.affiliation: Department of Biomedicine, Aarhus University, 8000, Aarhus C, Denmark. tan@biomed.au.dk.|Department of Rheumatology, Aarhus University Hospital, 8000, Aarhus C, Denmark. tan@biomed.au.dk.
authors.forename: Thomas
authors.initials: T
authors.lastname: Andersen
authors.affiliation: Department of Biomedicine, Aarhus University, 8000, Aarhus C, Denmark. rasmus.bak@biomed.au.dk.
authors.forename: Rasmus Otkjær
authors.initials: RO
authors.lastname: Bak
authors.affiliation: Department of Medicine, Division of Immunology and Rheumatology, Stanford School of Medicine, Stanford, CA, USA. gloyiu@stanford.edu.
authors.forename: Gloria
authors.initials: G
authors.lastname: Yiu
authors.affiliation: Department of Rheumatology, Aarhus University Hospital, 8000, Aarhus C, Denmark. chstsere@rm.dk.
authors.forename: Christian Møller
authors.initials: CM
authors.lastname: Sørensen
authors.affiliation: Department of Rheumatology, Aarhus University Hospital, 8000, Aarhus C, Denmark. stengaard@ki.au.dk.
authors.forename: Kristian
authors.initials: K
authors.lastname: Stengaard-Pedersen
authors.affiliation: Department of Biomedicine, Aarhus University, 8000, Aarhus C, Denmark. giehm@biomed.au.dk.
authors.forename: Jacob Giehm
authors.initials: JG
authors.lastname: Mikkelsen
authors.affiliation: Department of Medicine, Division of Immunology and Rheumatology, Stanford School of Medicine, Stanford, CA, USA. pjutz@stanford.edu.
authors.forename: Paul Joseph
authors.initials: PJ
authors.lastname: Utz
authors.affiliation: Department of Biomedicine, Aarhus University, 8000, Aarhus C, Denmark. holm@biomed.au.dk.
authors.forename: Christian Kanstrup
authors.initials: CK
authors.lastname: Holm
authors.affiliation: Department of Biomedicine, Aarhus University, 8000, Aarhus C, Denmark. bd@biomed.au.dk.|Department of Rheumatology, Aarhus University Hospital, 8000, Aarhus C, Denmark. bd@biomed.au.dk.
authors.forename: Bent
authors.initials: B
authors.lastname: Deleuran
mesh_terms: D000328:Adult; D002478:Cells, Cultured; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007378:Interleukins / Q000096:biosynthesis*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000175:diagnosis / Q000378:metabolism*; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis*; D008875:Middle Aged; D050796:STAT3 Transcription Factor / Q000096:biosynthesis*; D015398:Signal Transduction / Q000502:physiology; D000098546:Interleukin-21
chemical_list: D007378:Interleukins; C524942:MIRN155 microRNA, human; D035683:MicroRNAs; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000098546:Interleukin-21