title: Local synthesis of interferon-alpha in lupus nephritis is associated with type I interferons signature and LMP7 induction in renal tubular epithelial cells.
abstract: BACKGROUND
  Type I interferons are pivotal in the activation of autoimmune response in systemic lupus erythematous. However, the pathogenic role of interferon-alpha in patients affected by lupus nephritis remains uncertain. The aim of our study was to investigate the presence of a specific interferon signature in lupus nephritis and the effects of interferon-alpha at renal level.
  
  
  METHODS
  We performed immunohistochemical analysis for MXA-protein and in situ hybridization to detect interferon-alpha signature and production in human lupus nephritis. Through microarray studies, we analyzed the gene expression profile of renal tubular epithelial cells, stimulated with interferon-alpha. We validated microarray results through real-time polymerase chain reaction, flow cytometry on renal tubular epithelial cells, and through immunohistochemical analysis and confocal microscopy on renal biopsies.
  
  
  RESULTS
  Type I interferons signature was characterized by MXA-specific staining in renal tubular epithelial cells; in addition, in situ hybridization showed that renal tubular epithelial cells were the major producers of interferon-alpha, indicating a potential autocrine effect. Whole-genome expression profile showed interferon-alpha induced up-regulation of genes involved in innate immunity, protein ubiquitination and switching to immunoproteasome. In accordance with the in vitro data, class IV lupus nephritis showed up-regulation of the immunoproteasome subunit LMP7 in tubular epithelial cells associated with type I interferon signature.
  
  
  CONCLUSIONS
  Our data indicate that type I interferons might have a pathogenic role in lupus nephritis characterized by an autocrine effect of interferon-alpha on renal tubular epithelial cells. Therefore we hypothesize that inhibition of type I interferons might represent a therapeutic target to prevent tubulo-interstitial damage in patients with lupus nephritis.
authors.affiliation: Renal, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Piazza Giulio Cesare 11, 70124, Bari, Italy. giuseppe.castellano@uniba.it.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Castellano
authors.affiliation: Renal, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Piazza Giulio Cesare 11, 70124, Bari, Italy. c.cafiero@yahoo.it.
authors.forename: Cesira
authors.initials: C
authors.lastname: Cafiero
authors.affiliation: Renal, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Piazza Giulio Cesare 11, 70124, Bari, Italy. chiara.divella@libero.it.
authors.forename: Chiara
authors.initials: C
authors.lastname: Divella
authors.affiliation: C.A.R.S.O. Consortium, Valenzano, Bari, Italy. fabio.sallustio@uniba.it.
authors.forename: Fabio
authors.initials: F
authors.lastname: Sallustio
authors.affiliation: Renal, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Piazza Giulio Cesare 11, 70124, Bari, Italy. gigantem@libero.it.
authors.forename: Margherita
authors.initials: M
authors.lastname: Gigante
authors.affiliation: Renal, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Piazza Giulio Cesare 11, 70124, Bari, Italy. paola.pontrelli@uniba.it.
authors.forename: Paola
authors.initials: P
authors.lastname: Pontrelli
authors.affiliation: C.A.R.S.O. Consortium, Valenzano, Bari, Italy. g.depalma@nephro.uniba.it.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: De Palma
authors.affiliation: Renal, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Piazza Giulio Cesare 11, 70124, Bari, Italy. michelerossini@libero.it.
authors.forename: Michele
authors.initials: M
authors.lastname: Rossini
authors.affiliation: Renal, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy. giuseppe.grandaliano@unifg.it.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Grandaliano
authors.affiliation: Renal, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Piazza Giulio Cesare 11, 70124, Bari, Italy. loreto.gesualdo@uniba.it.
authors.forename: Loreto
authors.initials: L
authors.lastname: Gesualdo
mesh_terms: D001706:Biopsy; D015153:Blotting, Western; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007370:Interferon Type I / Q000096:biosynthesis*; D016898:Interferon-alpha / Q000096:biosynthesis*; D007684:Kidney Tubules / Q000378:metabolism* / Q000473:pathology; D008181:Lupus Nephritis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008285:Major Histocompatibility Complex; D018613:Microscopy, Confocal; D046988:Proteasome Endopeptidase Complex / Q000096:biosynthesis / Q000235:genetics*; D012313:RNA / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D012189:Retrospective Studies
chemical_list: D007370:Interferon Type I; D016898:Interferon-alpha; D012313:RNA; C077436:LMP7 protein; D046988:Proteasome Endopeptidase Complex