BMB Reports 2018; 51(10): 538-543  https://doi.org/10.5483/BMBRep.2018.51.10.181
PEP-1-paraoxonase 1 fusion protein prevents cytokine-induced cell destruction and impaired insulin secretion in rat insulinoma cells
Su Jin Lee1, Hyung Kyung Kang2, Yeon Joo Choi3, Won Sik Eum3, Jinseu Park3, Soo Young Choi3,* and Hyeok Yil Kwon1,*
1Department of Physiology, College of Medicine, Hallym University, Chuncheon 24252, 2Department of Physiology, College of Medicine, Korea University, Seoul 02841, 3Department of Biomedical Science and Research Institute of Bioscience and Biotechnology, Hallym University, Chuncheon 24252, Korea
Correspondence to: Hyeok Yil Kwon, Tel: +82-33-248-2584; Fax: +82-33-248-2580; E-mail: hykwon@hallym.ac.kr
Soo Young Choi, Tel: +82-33-248-2112; Fax: +82-33-256-3420; E-mail: sychoi@hallym.ac.kr
Received: August 3, 2018; Revised: August 24, 2018; Accepted: September 10, 2018; Published online: October 31, 2018.
© Korean Society for Biochemistry and Molecular Biology. All rights reserved.

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Abstract
Pancreatic beta cell destruction and dysfunction induced by cytokines is a major cause of type 1 diabetes. Paraoxonase 1 (PON1), an arylesterase with antioxidant activity, has been shown to play an important role in preventing the development of diabetes in transgenic mice. However, no studies have examined the anti-diabetic effect of PON1 delivered to beta cells using protein transduction. In this study, we expressed the cell-permeable PON1 fused with PEP-1 protein transduction domain (PEP-1-PON1) to investigate whether transduced PEP-1-PON1 protects beta cells against cytokine-induced cytotoxicity. PEP-1-PON1 was effectively delivered to INS-1 cells and prevented cytokine-induced cell destruction in a dose-dependent manner. Transduced PEP-1-PON1 significantly reduced the levels of reactive oxygen species (ROS) and nitric oxide (NO), DNA fragmentation, and expression of inflammatory mediators, endoplasmic reticulum (ER) stress proteins, and apoptosis-related proteins in cytokine-treated cells. Moreover, transduced PEP-1-PON1 restored the decrease in basal and glucose-stimulated insulin secretion induced by cytokines. These data indicate that PEP-1-PON1 protects beta cells from cytokine-induced cytotoxicity by alleviating oxidative/nitrosative stress, ER stress, and inflammation. Thus, PEP-1-mediated PON1 transduction might be an effective method to reduce the extent of destruction and dysfunction of pancreatic beta cells in autoimmune diabetes.
Keywords: Beta cell destruction, Cytokines, Diabetes, Insulin secretion, PEP-1-PON1


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