Inhibition of cytokine-induced β cell apoptosis via laccase and its therapeutic advantages for insulin-dependent diabetes mellitus, type 1 diabetes.
In pancreatic islets, free radical formation produced upon exposure to proinflammatory cytokines mediates β cell destruction, which ultimately leads to type 1 diabetes (T1D). In this study, we examined whether laccase, a family of the blue copper protein, can be successfully used to prevent β cells from cytokine-mediated apoptosis. Non-obese diabetic (NOD) mice were used for these experiments. In parallel, the RINm5f β cell line was employed as a model system for in vitro experiments. The results demonstrated that laccase effectively scavenged peroxinitrite, which can be formed by nitric oxide, and upregulated the expression of antioxidant enzymes, such as manganese superoxide dismutase (MnSOD) and catalase. Interestingly, laccase balanced pro- (Bax) and anti-apoptotic (Bcl-2) proteins in terms of both the mRNA and protein levels with a downregulation of cytochrome c protein in RINm5f cells. In addition, laccase maintained blood glucose concentrations at a normal level with a simultaneous increase in plasma insulin levels during the spontaneous induction of diabetes in NOD mice. In conclusion, the antioxidant potentials of laccase in scavenging free radicals and upregulation of antioxidant enzymes may exert its pro-survival effect by counteracting the increased intracellular oxidative stress, and, consequently, by inhibiting apoptosis induced by cytokine-mediated activation during the course of T1D.
Division of Marine Molecular Biotechnology, Gangneung-Wonju National University, 120 Gangneung Daehangno, Gangneung, Gangwon 210–702, Republic of Korea.
Seong Soo
SS
Joo
Do Ik
DI
Lee
Kwang Woo
KW
Hwang
D000818:Animals; D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D001786:Blood Glucose / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D007328:Insulin / Q000097:blood; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000502:physiology; D042845:Laccase / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D016688:Mice, Inbred NOD; D018384:Oxidative Stress / Q000187:drug effects*; D030421:Peroxynitrous Acid / Q000378:metabolism; D008517:Phytotherapy; D020072:Polyporales / Q000737:chemistry*; D051381:Rats; D015854:Up-Regulation; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
D000975:Antioxidants; D001786:Blood Glucose; D016207:Cytokines; D007328:Insulin; D051028:bcl-2-Associated X Protein; D030421:Peroxynitrous Acid; D045304:Cytochromes c; D042845:Laccase