The role of nitric oxide and the unfolded protein response in cytokine-induced β-cell death

Kari T. Chambers, Julie A. Unverferth, Sarah M. Weber, Ronald Wek, Fumihiko Urano, John A. Corbett

Research output: Contribution to journalArticle

61 Citations (Scopus)

Abstract

OBJECTIVE - The unfolded protein response (UPR) is a conserved cellular response designed to alleviate damage and promote survival of cells experiencing stress; however, prolonged UPR activation can result in apoptotic cell death. The UPR, activated by cytokine-induced nitric oxide (NO) production, has been proposed to mediate β-cell death in response to cytokines. In this study, the role of UPR activation in cytokine-induced β-cell death was examined. RESEARCH DESIGN AND METHODS - The effects of cytokine treatment of rat and human islets and RINm5F cells on UPR activation, NO production, and cell viability were examined using molecular and biochemical methodologies. RESULTS-UPR activation correlates with β-cell death in interleukin (IL)-1-treated rat islets. NO mediates both cytokine-induced UPR activation and β-cell death as NO synthase inhibitors attenuate each of these IL-1-stimulated events. Importantly, cytokines and tunicamycin, a classical UPR activator, induce β-cell death by different mechanisms. Cell death in response to the classical UPR activator is associated with a 2.5-fold increase in caspase-3 activity, while IL-1 fails to stimulate caspase-3 activity. In addition, cell death is enhanced by ∼35% in tunicamycin-treated cells expressing an S51A eIF2α mutant that cannot be phosphorylated or in cells lacking PERK (protein kinase regulated by RNA/endoplasmic reticulum-like kinase). In contrast, neither the absence of PERK nor the expression of the S51A eIF2α mutant affects the levels of cytokine-induced death. CONCLUSIONS - While cytokine-induced β-cell death temporally correlates with UPR activation, the lack of caspase activity and the ability of NO to attenuate caspase activity suggest that prolonged UPR activation does not mediate cytokine-induced β-cell death.

Original languageEnglish
Pages (from-to)124-132
Number of pages9
JournalDiabetes
Volume57
Issue number1
DOIs
StatePublished - Jan 2008

Fingerprint

Unfolded Protein Response
Nitric Oxide
Cell Death
Cytokines
Interleukin-1
Tunicamycin
Caspases
Caspase 3
Cell Survival
Islets of Langerhans
Nitric Oxide Synthase
Endoplasmic Reticulum
Protein Kinases
Research Design
Phosphotransferases

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Chambers, K. T., Unverferth, J. A., Weber, S. M., Wek, R., Urano, F., & Corbett, J. A. (2008). The role of nitric oxide and the unfolded protein response in cytokine-induced β-cell death. Diabetes, 57(1), 124-132. https://doi.org/10.2337/db07-0944

The role of nitric oxide and the unfolded protein response in cytokine-induced β-cell death. / Chambers, Kari T.; Unverferth, Julie A.; Weber, Sarah M.; Wek, Ronald; Urano, Fumihiko; Corbett, John A.

In: Diabetes, Vol. 57, No. 1, 01.2008, p. 124-132.

Research output: Contribution to journalArticle

Chambers, KT, Unverferth, JA, Weber, SM, Wek, R, Urano, F & Corbett, JA 2008, 'The role of nitric oxide and the unfolded protein response in cytokine-induced β-cell death', Diabetes, vol. 57, no. 1, pp. 124-132. https://doi.org/10.2337/db07-0944
Chambers, Kari T. ; Unverferth, Julie A. ; Weber, Sarah M. ; Wek, Ronald ; Urano, Fumihiko ; Corbett, John A. / The role of nitric oxide and the unfolded protein response in cytokine-induced β-cell death. In: Diabetes. 2008 ; Vol. 57, No. 1. pp. 124-132.
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AU - Corbett, John A.

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N2 - OBJECTIVE - The unfolded protein response (UPR) is a conserved cellular response designed to alleviate damage and promote survival of cells experiencing stress; however, prolonged UPR activation can result in apoptotic cell death. The UPR, activated by cytokine-induced nitric oxide (NO) production, has been proposed to mediate β-cell death in response to cytokines. In this study, the role of UPR activation in cytokine-induced β-cell death was examined. RESEARCH DESIGN AND METHODS - The effects of cytokine treatment of rat and human islets and RINm5F cells on UPR activation, NO production, and cell viability were examined using molecular and biochemical methodologies. RESULTS-UPR activation correlates with β-cell death in interleukin (IL)-1-treated rat islets. NO mediates both cytokine-induced UPR activation and β-cell death as NO synthase inhibitors attenuate each of these IL-1-stimulated events. Importantly, cytokines and tunicamycin, a classical UPR activator, induce β-cell death by different mechanisms. Cell death in response to the classical UPR activator is associated with a 2.5-fold increase in caspase-3 activity, while IL-1 fails to stimulate caspase-3 activity. In addition, cell death is enhanced by ∼35% in tunicamycin-treated cells expressing an S51A eIF2α mutant that cannot be phosphorylated or in cells lacking PERK (protein kinase regulated by RNA/endoplasmic reticulum-like kinase). In contrast, neither the absence of PERK nor the expression of the S51A eIF2α mutant affects the levels of cytokine-induced death. CONCLUSIONS - While cytokine-induced β-cell death temporally correlates with UPR activation, the lack of caspase activity and the ability of NO to attenuate caspase activity suggest that prolonged UPR activation does not mediate cytokine-induced β-cell death.

AB - OBJECTIVE - The unfolded protein response (UPR) is a conserved cellular response designed to alleviate damage and promote survival of cells experiencing stress; however, prolonged UPR activation can result in apoptotic cell death. The UPR, activated by cytokine-induced nitric oxide (NO) production, has been proposed to mediate β-cell death in response to cytokines. In this study, the role of UPR activation in cytokine-induced β-cell death was examined. RESEARCH DESIGN AND METHODS - The effects of cytokine treatment of rat and human islets and RINm5F cells on UPR activation, NO production, and cell viability were examined using molecular and biochemical methodologies. RESULTS-UPR activation correlates with β-cell death in interleukin (IL)-1-treated rat islets. NO mediates both cytokine-induced UPR activation and β-cell death as NO synthase inhibitors attenuate each of these IL-1-stimulated events. Importantly, cytokines and tunicamycin, a classical UPR activator, induce β-cell death by different mechanisms. Cell death in response to the classical UPR activator is associated with a 2.5-fold increase in caspase-3 activity, while IL-1 fails to stimulate caspase-3 activity. In addition, cell death is enhanced by ∼35% in tunicamycin-treated cells expressing an S51A eIF2α mutant that cannot be phosphorylated or in cells lacking PERK (protein kinase regulated by RNA/endoplasmic reticulum-like kinase). In contrast, neither the absence of PERK nor the expression of the S51A eIF2α mutant affects the levels of cytokine-induced death. CONCLUSIONS - While cytokine-induced β-cell death temporally correlates with UPR activation, the lack of caspase activity and the ability of NO to attenuate caspase activity suggest that prolonged UPR activation does not mediate cytokine-induced β-cell death.

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