title: Inflammatory stress of pancreatic beta cells drives release of extracellular heat-shock protein 90α.
abstract: A major obstacle in predicting and preventing the development of autoimmune type 1 diabetes (T1D) in at-risk individuals is the lack of well-established early biomarkers indicative of ongoing beta cell stress during the pre-clinical phase of disease. Recently, serum levels of the α cytoplasmic isoform of heat-shock protein 90 (hsp90) were shown to be elevated in individuals with new-onset T1D. We therefore hypothesized that hsp90α could be released from beta cells in response to cellular stress and inflammation associated with the earliest stages of T1D. Here, human beta cell lines and cadaveric islets released hsp90α in response to stress induced by treatment with a combination of pro-inflammatory cytokines including interleukin-1β, tumour necrosis factor-α and interferon-γ. Mechanistically, hsp90α release was found to be driven by cytokine-induced endoplasmic reticulum stress mediated by c-Jun N-terminal kinase (JNK), a pathway that can eventually lead to beta cell apoptosis. Cytokine-induced beta cell hsp90α release and JNK activation were significantly reduced by pre-treating cells with the endoplasmic reticulum stress-mitigating chemical chaperone tauroursodeoxycholic acid. The hsp90α release by cells may therefore be a sensitive indicator of stress during inflammation and a useful tool in assessing therapeutic mitigation of cytokine-induced cell damage linked to autoimmunity.
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Gail J
authors.initials: GJ
authors.lastname: Ocaña
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Liliana
authors.initials: L
authors.lastname: Pérez
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Lynette
authors.initials: L
authors.lastname: Guindon
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Sarah N
authors.initials: SN
authors.lastname: Deffit
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.|Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Carmella
authors.initials: C
authors.lastname: Evans-Molina
authors.affiliation: Department of Molecular and Cellular Endocrinology, Beckman Research Institute of City of Hope, Duarte, CA, USA.
authors.forename: Debbie C
authors.initials: DC
authors.lastname: Thurmond
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Janice S
authors.identifier: 0000-0002-0403-8001
authors.initials: JS
authors.lastname: Blum
mesh_terms: D000328:Adult; D002478:Cells, Cultured; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D050417:Insulin-Secreting Cells / Q000276:immunology* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress / Q000276:immunology
chemical_list: D018841:HSP90 Heat-Shock Proteins; C533585:HSP90AA2P protein, human
keywords: Jun N-terminal kinase; endoplasmic reticulum stress; heat-shock protein 90; inflammation; type 1 diabetes