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The Role of Nitric Oxide and the Unfolded Protein Response in Cytokine Induced ß-cell Death

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

From the *Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, Saint Louis, MO 63104,
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202,
the Program in Gene Function and Expression, University of Massachusetts Medical School, North Worcester, MA 01605

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 production, has been proposed to mediate ß-cell death in response to cytokines. In this study, the role of UPR activation in cytokine-induced ß-cell death was examined.

Research Design and Methods.: The effects of cytokine treatment of rat and human islets and RINm5F cells on UPR activation, nitric oxide production and cell viability was examined using molecular and biochemical methodologies.

Results.: UPR activation correlates with ß-cell death in IL-1 treated rat islets. Nitric oxide mediates both cytokine-induced UPR activation and ß-cell death as NOS inhibitors attenuate each of these IL-1 stimulated events. Importantly, cytokines and tunicamycin, a classical UPR activator, induce ß-cell death by different mechanisms. Cell death in response to the classical UPR activator is associated with 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 eIF2 mutant that cannot be phosphorylated or cells lacking PERK. In contrast, neither the absence of PERK nor the expression of the S51A eIF2 mutant affects the levels of cytokine-induced death.

Conclusions.: While cytokine-induced ß-cell death temporally correlates with UPR activation, the lack of caspase activity and the ability of nitric oxide to attenuate caspase activity suggest that prolonged UPR activation does not mediate cytokine-induced ß-cell death.

Key Words: Nitric oxide • ß-cell • diabetes • UPR • cytokines • cell death.

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