title: SerpinB9 expression in human renal tubular epithelial cells is induced by triggering of the viral dsRNA sensors TLR3, MDA5 and RIG-I.
abstract: BACKGROUND
  Serine protease inhibitor B9 (serpinB9) protects against granzyme B-mediated apoptosis and could help to reduce tubular damage under inflammatory conditions like interstitial nephritis. Previously, we found that tubular serpinB9 expression was increased during subclinical rejection. Here, we studied the regulation of serpinB9 expression in tubular epithelial cells (TECs) under inflammatory conditions.
  
  
  METHODS
  SerpinB9 expression was analysed on messenger RNA (mRNA), and protein levels in primary human TECs were stimulated with various cytokines and pattern recognition receptor ligands and in kidney transplant biopsies obtained during different types of viral infection.
  
  
  RESULTS
  Of the inflammatory stimuli tested, only the double-stranded RNA (dsRNA) analogue poly(I:C) promoted serpinB9 mRNA and protein expression. We found that TECs express the viral dsRNA receptors Toll-like receptor 3 (TLR3), melanoma differentiation-associated gene 5 (MDA5) and retinoic acid-inducible gene-I (RIG-I). dsRNA receptor ligands enhanced serpinB9 expression, which involved nuclear factor-kappaB (NF-κB) activation, did not require Type I interferon production and was a direct result of dsRNA receptor-induced gene transcription. In kidney transplants, serpinB9 transcription was increased during infection with cytomegalovirus, Epstein-Barr virus or BK virus compared to stable grafts. Immunohistochemistry showed that tubuli and lymphocytes expressed the inhibitor.
  
  
  CONCLUSIONS
  SerpinB9 expression in human TECs is induced by triggering of the viral dsRNA sensors TLR3, MDA5 and RIG-I. Viral dsRNA may increase the threshold for granzyme B-mediated apoptosis in TECs via serpinB9 upregulation and thus help to protect the kidney against cytotoxic insults during viral infection.
authors.affiliation: Department of Experimental Immunology, Renal Transplant Unit, Academic Medical Center, Amsterdam, The Netherlands. K.M.Heutinck@amc.uva.nl
authors.forename: Kirstin M
authors.initials: KM
authors.lastname: Heutinck
authors.forename: Jorien
authors.initials: J
authors.lastname: Kassies
authors.forename: Sandrine
authors.initials: S
authors.lastname: Florquin
authors.forename: Ineke J M
authors.initials: IJ
authors.lastname: ten Berge
authors.forename: Jörg
authors.initials: J
authors.lastname: Hamann
authors.forename: Ajda T
authors.initials: AT
authors.lastname: Rowshani
mesh_terms: D001739:BK Virus / Q000235:genetics; D001706:Biopsy; D015153:Blotting, Western; D002478:Cells, Cultured; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D020031:Epstein-Barr Virus Infections / Q000235:genetics / Q000378:metabolism / Q000821:virology; D004854:Herpesvirus 4, Human / Q000235:genetics; D006801:Humans; D007124:Immunoenzyme Techniques; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D000072640:Interferon-Induced Helicase, IFIH1; D007674:Kidney Diseases / Q000378:metabolism / Q000601:surgery / Q000821:virology; D016030:Kidney Transplantation; D007684:Kidney Tubules / Q000166:cytology / Q000378:metabolism*; D008214:Lymphocytes / Q000166:cytology / Q000378:metabolism; D011070:Poly I-C / Q000494:pharmacology; D027601:Polyomavirus Infections / Q000235:genetics / Q000378:metabolism / Q000821:virology; D012330:RNA, Double-Stranded / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D012367:RNA, Viral / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D011971:Receptors, Immunologic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015843:Serpins / Q000235:genetics / Q000378:metabolism*; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000378:metabolism*; D014412:Tumor Virus Infections / Q000235:genetics / Q000378:metabolism / Q000821:virology
chemical_list: D018836:Inflammation Mediators; D012330:RNA, Double-Stranded; D012333:RNA, Messenger; D012367:RNA, Viral; D011971:Receptors, Immunologic; C102316:SERPINB9 protein, human; D015843:Serpins; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; C452820:RIGI protein, human; C452815:IFIH1 protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1; D011070:Poly I-C