Inflammatory stress of pancreatic beta cells drives release of extracellular heat shock protein 90α

Authors

  • Gail J. Ocaña,

    1. Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA
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  • Liliana Pérez,

    1. Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA
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  • Lynette Guindon,

    1. Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA
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  • Sarah N. Deffit,

    1. Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA
    Current affiliation:
    1. Medical Sciences Program, Indiana University School of Medicine, Bloomington, IN, USA
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  • Carmella Evans-Molina,

    1. Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
    2. Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
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  • Debbie C. Thurmond,

    1. Department of Molecular and Cellular Endocrinology, Beckman Research Institute of City of Hope, Duarte, CA, USA
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  • Janice S. Blum

    Corresponding author
    1. Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA
    • Corresponding Author: Janice S. Blum

      Address: 635 Barnhill Drive, Indianapolis, IN 46202

      Telephone: (317) 278-1715

      Fax: (317) 278-3331

      jblum@iupui.edu

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  • This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/imm.12723

Summary

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 alpha cytoplasmic isoform of heat shock protein (HSP) 90 were shown to be elevated in individuals with new-onset T1D. We therefore hypothesized 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 IL-1β, TNF-α, and IFN-γ. Mechanistically, HSP90α release was found to be driven by cytokine-induced endoplasmic reticulum (ER) 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 ER stress-mitigating chemical chaperone tauroursodeoxycholic acid (TUDCA). HSP90α release by cells may thus be a sensitive indicator of stress during inflammation and a useful tool in assessing therapeutic mitigation of cytokine-induced cell damage linked to autoimmunity.

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