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Cytokine-induced β-cell death is independent of endoplasmic reticulum stress signaling

From the ¹Diabetes and Obesity Research Program and
the ²Immunology and Inflammation Research Program, Garvan Institute of Medical Research, St Vincent's Hospital, Sydney, NSW, Australia

Objective: Cytokines contribute to β-cell destruction in type 1 diabetes. Endoplasmic reticulum (ER) stress-mediated apoptosis has been proposed as a mechanism for β-cell death. We tested whether ER stress was necessary for cytokine-induced β-cell death and also whether ER stress gene activation was present in β-cells of the non-obese diabetic (NOD) mouse model of type 1 diabetes.

Research Design And Methods: INS-1 β-cells or rat islets were treated with the chemical chaperone, phenyl butyric acid (PBA) and exposed or not to interleukin-1β (IL-1β) and -interferon (IFN-). Small interfering RNA was used to silence CHOP expression in INS-1 β-cells. Additionally, the role of ER stress in lipid-induced cell death was assessed.

Results: Cytokines and palmitate triggered ER stress in β-cells as evidenced by increased phosphorylation of PERK, EIF2 and JNK, and increased expression of ATF4 and CHOP. PBA treatment attenuated ER stress, but JNK phosphorylation was reduced only in response to palmitate, and not in response to cytokines. PBA had no effect on cytokine-induced cell death, but was associated with protection against palmitate-induced cell death. Similarly, siRNA-mediated reduction in CHOP expression protected against palmitate-, but not against cytokine-induced cell death. In NOD islets, mRNA levels of several ER stress genes were reduced (ATF4, BiP, GRP94, p58, XBP-1 splicing) or unchanged (CHOP, Edem1).

Conclusions: While both cytokines and palmitate can induce ER stress, our results suggest that, in contrast to lipoapoptosis, the PERK-ATF4-CHOP ER stress-signaling pathway is not necessary for cytokine-induced β-cell death.

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