Local synthesis of interferon-alpha in lupus nephritis is associated with type I interferons signature and LMP7 induction in renal tubular epithelial cells.

Item request has been placed! ×
Item request cannot be made. ×
loading   Processing Request
Read More Add to Saved list
  • Additional Information
    • Source:
      Publisher: BioMed Central Country of Publication: England NLM ID: 101154438 Publication Model: Electronic Cited Medium: Internet ISSN: 1478-6362 (Electronic) Linking ISSN: 14786354 NLM ISO Abbreviation: Arthritis Res Ther Subsets: MEDLINE
    • Publication Information:
      Original Publication: London : BioMed Central, 2003-
    • Subject Terms:
      Gene Expression Regulation*; Interferon Type I/*biosynthesis ; Interferon-alpha/*biosynthesis ; Kidney Tubules/*metabolism ; Lupus Nephritis/*genetics ; Proteasome Endopeptidase Complex/*genetics ; RNA/*genetics; Biopsy ; Blotting, Western ; Cells, Cultured ; Epithelial Cells/metabolism ; Humans ; Immunohistochemistry ; In Situ Hybridization ; Kidney Tubules/pathology ; Lupus Nephritis/metabolism ; Lupus Nephritis/pathology ; Major Histocompatibility Complex ; Microscopy, Confocal ; Proteasome Endopeptidase Complex/biosynthesis ; Real-Time Polymerase Chain Reaction ; Retrospective Studies
    • Abstract:
      Introduction: 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.
    • References:
      N Engl J Med. 2011 Dec 1;365(22):2110-21. (PMID: 22129255)
      J Am Soc Nephrol. 1991 Jul;2(1):13-26. (PMID: 1912411)
      Arthritis Res Ther. 2011;13(6):250. (PMID: 22192660)
      Arthritis Res Ther. 2010;12 Suppl 1:S3. (PMID: 20392290)
      Curr Opin Immunol. 2012 Dec;24(6):665-70. (PMID: 22999705)
      Nat Rev Nephrol. 2012 Dec;8(12):709-17. (PMID: 23147758)
      Arthritis Rheum. 2013 Apr;65(4):1011-21. (PMID: 23400715)
      Clin Immunol. 2013 Jun;147(3):216-22. (PMID: 23290784)
      Clin Immunol. 2013 Sep;148(3):303-12. (PMID: 23566912)
      J Am Soc Nephrol. 2013 Sep;24(9):1357-66. (PMID: 23929771)
      Kidney Int. 2010 May;77(10):848-54. (PMID: 20237459)
      Mol Immunol. 2010 Jul;47(11-12):2129-37. (PMID: 20417969)
      Gut. 2010 Jul;59(7):896-906. (PMID: 20581238)
      Proc Natl Acad Sci U S A. 2010 Oct 26;107(43):18599-604. (PMID: 20937868)
      J Am Soc Nephrol. 2010 Dec;21(12):2028-35. (PMID: 21051743)
      Cell Res. 2011 Jan;21(1):86-102. (PMID: 21102550)
      Kidney Int. 2011 Jun;79(11):1228-35. (PMID: 21346723)
      Crit Rev Biochem Mol Biol. 2011 Jun;46(3):229-39. (PMID: 21476929)
      Ups J Med Sci. 2011 Nov;116(4):227-37. (PMID: 22066971)
      Science. 2001 Nov 16;294(5546):1540-3. (PMID: 11711679)
      J Exp Med. 2003 Mar 17;197(6):711-23. (PMID: 12642603)
      J Clin Invest. 2005 Feb;115(2):407-17. (PMID: 15668740)
      Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50. (PMID: 16199517)
      J Biol Chem. 2006 Jul 7;281(27):18684-90. (PMID: 16675465)
      Immunity. 2006 Sep;25(3):383-92. (PMID: 16979570)
      J Virol. 2007 Jul;81(14):7776-85. (PMID: 17494065)
      Mol Immunol. 2008 Jan;45(1):259-65. (PMID: 17570528)
      Nat Rev Mol Cell Biol. 2008 Dec;9(12):971-80. (PMID: 19023284)
      J Biol Chem. 2009 Jan 9;284(2):807-17. (PMID: 19017631)
      Am J Kidney Dis. 2009 Mar;53(3):467-74. (PMID: 19167798)
      Nat Med. 2009 Jul;15(7):781-7. (PMID: 19525961)
      J Immunol. 2009 Nov 1;183(9):6021-9. (PMID: 19812195)
      FASEB J. 2010 Feb;24(2):514-25. (PMID: 19843711)
      Trends Mol Med. 2010 Feb;16(2):47-57. (PMID: 20138006)
      Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9440-5. (PMID: 12883005)
      J Am Soc Nephrol. 2004 Feb;15(2):241-50. (PMID: 14747370)
      J Am Soc Nephrol. 2004 Apr;15(4):854-67. (PMID: 15034087)
      Immunity. 2004 May;20(5):539-50. (PMID: 15142523)
      J Clin Invest. 2004 Jun;113(12):1722-33. (PMID: 15199407)
      J Cell Sci. 2004 Jul 15;117(Pt 16):3615-24. (PMID: 15252129)
      Arthritis Rheum. 2012 Feb;64(2):493-503. (PMID: 21905015)
    • Accession Number:
      0 (Interferon Type I)
      0 (Interferon-alpha)
      63231-63-0 (RNA)
      EC 3.4.25.1 (LMP7 protein)
      EC 3.4.25.1 (Proteasome Endopeptidase Complex)
    • Publication Date:
      Date Created: 20150419 Date Completed: 20160108 Latest Revision: 20181113
    • Publication Date:
      20240829
    • Accession Number:
      PMC4389585
    • Accession Number:
      10.1186/s13075-015-0588-3
    • Accession Number:
      25889472