PEP-1-paraoxonase 1 fusion protein prevents cytokine-induced cell destruction and impaired insulin secretion in rat insulinoma cells
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초록
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.
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.
참고문헌 (27)
- Eizirik DL, "A choice of death: the signal-transduction of immune-mediated beta-cell apoptosis", Diabetologia, 44, pp.2115~2133 (2001)[DOI]
- Padgett LE, "The role of reactive oxygen species and proinflammatory cytokines in type 1 diabetes pathogenesis", Ann NY Acad Sci, 1281, pp.16~35 (2013)[DOI]
- Storling J, "Nitric oxide contributes to cytokine-induced apoptosis in pancreatic beta-cells via potentiation of JNK activity and inhibition of Akt", Diabetologia, 48, pp.2039~2050 (2005)[DOI]
- Grunnet LG, "Proinflammatory cytokines activate the intrinsic apoptotic pathway in beta-cells", Diabetes, 58, pp.1807~1815 (2009)[DOI]
- Hayek T, "Macrophage foam-cell formation in streptozotocin-induced diabetic mice: stimulatory effect of glucose", Atherosclerosis, 183, pp.25~33 (2005)[DOI]
- Ahmed FN, "Lipid peroxidation and serum antioxidant enzymes in patients with type 2 diabetes mellitus", Ann NY Acad Sci, 1084, pp.481~489 (2006)[DOI]
- Kulka M, "A review of paraoxonase 1 properties and diagnostic applications", Pol J Vet Sci, 19, pp.225~232 (2016)[DOI]
- Mackness M, "Human paraoxonase-1 (PON1): Gene structure and expression, promiscuous activities and multiple physiological roles", Gene, 567, pp.12~21 (2015)[DOI]
- Rozenberg O, "Paraoxonase 1 (PON1) attenuates diabetes development in mice through its antioxidative properties", Free Radic Biol Med, 44, pp.1951~1959 (2008)[DOI]
- Koren-Gluzer M, "The antioxidant HDL-associated Paraoxonase 1 (PON1) attenuates diabetes development and stimulates <TEX>${\beta}$<", TEX>-cell insulin release, 2011, pp.219, 510~518
- Kota SK, "Implications of serum paraoxonase activity in obesity, diabetes mellitus, and dyslipidemia", Indian J Endocrinol Metab, 17, pp.402~412 (2013)[DOI]
- Lortz S, "Protection of insulin-producing RINm5F cells against cytokine-mediated toxicity through overexpression of antioxidant enzymes", Diabetes, 49, pp.1123~1130 (2000)[DOI]
- Eum WS, "HIV-1 Tat-mediated protein transduction of Cu, Zn-superoxide dismutase into pancreatic <TEX>${\beta}$<", TEX>-cells in vitro and in vivo, 2004, pp.37, 339~349
- Snyder EL, "Recent advances in the use of protein transduction domains for the delivery of peptides, proteins and nucleic acids in vivo", Expert Opin Drug Deliv, 2, pp.43~51 (2005)[DOI]
- Lee SJ, "Tat-biliverdin reductase A protects INS-1 cells from human islet amyloid polypeptide-induced cytotoxicity by alleviating oxidative stress and ER stress", Cell Biol Int, 41, pp.514~524 (2017)[DOI]
- Lenzen S, "Low antioxidant enzyme gene expression in pancreatic islets compared with various other mouse tissues", Free Radic Biol Med, 20, pp.463~466 (1996)[DOI]
- Meredith M, "Dual functional effects of interleukin-1beta on purine nucleotides and insulin secretion in rat islets and INS-1 cells", Diabetes, 45, pp.1783~1791 (1996)[DOI]
- Chen M, "Lisofylline, a novel anti-inflammatory agent, protects pancreatic <TEX>${\beta}$<", TEX>-cells from proinflammatory cytokine damage by promoting mitochondrial metabolism, 2002, pp.143, 2341~2348
- Ho E, "Antioxidant, NFkappaB activation, and diabetogenesis", Proc Soc Exp Biol, 222, pp.205~213 (1999)[DOI]
- Corbett JA, "Tyrosine kinase inhibitors prevent cytokine-induced expression of iNOS and COX-2 by human islets", Am J Physiol, 270, pp.C1581~C1587 (1996)[DOI]
- Eizirik DL, "The role for endoplasmic reticulum stress in diabetes mellitus", Endo Rev, 29, pp.42~61 (2008)[DOI]
- Xu C, "Endoplasmic reticulum stress: cell life and death decisions", J Clin Invest, 115, pp.2656~2664 (2005)[DOI]
- Brozzi F, "ER stress and the decline and fall of pancreatic beta cells in type 1 diabetes", Ups J Med Sci, 121, pp.133~139 (2016)[DOI]
- Zhang K, "Identification and characterization of endoplasmic reticulum stress-induced apoptosis in vivo", Methods Enzymol, 442, pp.395~419 (2008)
- Urano F, "Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1", Science, 287, pp.664~666 (2000)[DOI]
- Kim MJ, "PEP-1-PON1 protein regulates inflammatory response in Raw 264.7 macrophages and ameliorates inflammation in a TPA-induced animal model", PLoS ONE, 9, pp.e86034~ (2014)[DOI]
- Misko TP, "A fluorometric assay for the measurement of nitrite in biological samples", Anal Biochem, 214, pp.11~16 (1993)[DOI]