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

Gail J. Ocaña, Liliana Pérez, Lynette Guindon, Sarah N. Deffit, Carmella Evans-Molina, Debbie C. Thurmond, Janice S. Blum

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)198-210
Number of pages13
JournalImmunology
Volume151
Issue number2
DOIs
StatePublished - Jun 2017

Keywords

  • Jun N-terminal kinase
  • endoplasmic reticulum stress
  • heat-shock protein 90
  • inflammation
  • type 1 diabetes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Fingerprint Dive into the research topics of 'Inflammatory stress of pancreatic beta cells drives release of extracellular heat-shock protein 90α'. Together they form a unique fingerprint.

Cite this