title: Interleukin-1 receptor-mediated inflammation impairs the heat shock response of human mesothelial cells.
abstract: Bioincompatibility of peritoneal dialysis fluids (PDF) limits their use in renal replacement therapy. PDF exposure harms mesothelial cells but induces heat shock proteins (HSP), which are essential for repair and cytoprotection. We searched for cellular pathways that impair the heat shock response in mesothelial cells after PDF-exposure. In a dose-response experiment, increasing PDF-exposure times resulted in rapidly increasing mesothelial cell damage but decreasing HSP expression, confirming impaired heat shock response. Using proteomics and bioinformatics, simultaneously activated apoptosis-related and inflammation-related pathways were identified as candidate mechanisms. Testing the role of sterile inflammation, addition of necrotic cell material to mesothelial cells increased, whereas addition of the interleukin-1 receptor (IL-1R) antagonist anakinra to PDF decreased release of inflammatory cytokines. Addition of anakinra during PDF exposure resulted in cytoprotection and increased chaperone expression. Thus, activation of the IL-1R plays a pivotal role in impairment of the heat shock response of mesothelial cells to PDF. Danger signals from injured cells lead to an elevated level of cytokine release associated with sterile inflammation, which reduces expression of HSP and other cytoprotective chaperones and exacerbates PDF damage. Blocking the IL-1R pathway might be useful in limiting damage during peritoneal dialysis.
authors: Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
authors: Klaus
authors: K
authors: Kratochwill
authors: Michael
authors: M
authors: Lechner
authors: Anton Michael
authors: AM
authors: Lichtenauer
authors: Rebecca
authors: R
authors: Herzog
authors: Hans Christian
authors: HC
authors: Lederhuber
authors: Christian
authors: C
authors: Siehs
authors: Michaela
authors: M
authors: Endemann
authors: Bernd
authors: B
authors: Mayer
authors: Andreas
authors: A
authors: Rizzi
authors: Christoph
authors: C
authors: Aufricht
mesh_terms: D001672:Biocompatible Materials; D019295:Computational Biology / Q000379:methods; D016207:Cytokines / Q000378:metabolism; D015180:Electrophoresis, Gel, Two-Dimensional / Q000379:methods; D004848:Epithelium / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000378:metabolism*; D018869:Heat-Shock Response; D006801:Humans; D007249:Inflammation; D007375:Interleukin-1 / Q000378:metabolism*; D013058:Mass Spectrometry / Q000379:methods; D008954:Models, Biological; D010530:Peritoneal Dialysis; D040901:Proteomics / Q000379:methods; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D001672:Biocompatible Materials; D016207:Cytokines; D006360:Heat-Shock Proteins; D007375:Interleukin-1; D017472:Receptors, Interleukin-1