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 Blum

Research output: Contribution to journalArticle

5 Citations (Scopus)

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)
JournalImmunology
DOIs
StateAccepted/In press - 2017

Fingerprint

HSP90 Heat-Shock Proteins
Insulin-Secreting Cells
Type 1 Diabetes Mellitus
Cytokines
Endoplasmic Reticulum Stress
Inflammation
JNK Mitogen-Activated Protein Kinases
Autoimmunity
Interleukin-1
Interferons
Protein Isoforms
Phosphotransferases
Tumor Necrosis Factor-alpha
Biomarkers
Apoptosis
Cell Line
Serum

Keywords

  • Endoplasmic reticulum stress
  • Heat-shock protein 90
  • Inflammation
  • Jun N-terminal kinase
  • Type 1 diabetes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Inflammatory stress of pancreatic beta cells drives release of extracellular heat-shock protein 90α. / Ocaña, Gail J.; Pérez, Liliana; Guindon, Lynette; Deffit, Sarah N.; Evans-Molina, Carmella; Thurmond, Debbie C.; Blum, Janice.

In: Immunology, 2017.

Research output: Contribution to journalArticle

Ocaña, Gail J. ; Pérez, Liliana ; Guindon, Lynette ; Deffit, Sarah N. ; Evans-Molina, Carmella ; Thurmond, Debbie C. ; Blum, Janice. / Inflammatory stress of pancreatic beta cells drives release of extracellular heat-shock protein 90α. In: Immunology. 2017.
@article{14f712bcb66e424c94ca705015b103ee,
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.",
keywords = "Endoplasmic reticulum stress, Heat-shock protein 90, Inflammation, Jun N-terminal kinase, Type 1 diabetes",
author = "Oca{\~n}a, {Gail J.} and Liliana P{\'e}rez and Lynette Guindon and Deffit, {Sarah N.} and Carmella Evans-Molina and Thurmond, {Debbie C.} and Janice Blum",
year = "2017",
doi = "10.1111/imm.12723",
language = "English (US)",
journal = "Immunology",
issn = "0019-2805",
publisher = "Wiley-Blackwell",

}

TY - JOUR

T1 - Inflammatory stress of pancreatic beta cells drives release of extracellular heat-shock protein 90α

AU - Ocaña, Gail J.

AU - Pérez, Liliana

AU - Guindon, Lynette

AU - Deffit, Sarah N.

AU - Evans-Molina, Carmella

AU - Thurmond, Debbie C.

AU - Blum, Janice

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

KW - Endoplasmic reticulum stress

KW - Heat-shock protein 90

KW - Inflammation

KW - Jun N-terminal kinase

KW - Type 1 diabetes

UR - http://www.scopus.com/inward/record.url?scp=85015218732&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85015218732&partnerID=8YFLogxK

U2 - 10.1111/imm.12723

DO - 10.1111/imm.12723

M3 - Article

C2 - 28190264

AN - SCOPUS:85015218732

JO - Immunology

JF - Immunology

SN - 0019-2805

ER -