beta cell cytoprotective strategies: establishing the relative roles for iNOS and ROS.
Cytokine-induced beta cell destruction may be mediated by the generation of nitric oxide and/or reactive oxygen species. The relative importance of NO and ROS in cytokine-induced beta cell pathophysiology remains unclear. This investigation evaluates and contrasts the cytoprotective potential of antioxidant gene transfer, versus NF-kappaB inhibition, using a degradation-resistant mutant of IkappaBalpha. NF-kappaB inhibition conferred significant protection against cytokine-induced damage whereas antioxidant overexpression failed to provide protection. Conferred cytoprotection was associated with a suppression of iNOS activation and nitrite accumulation. Our data implicates iNOS, as opposed to ROS, as the pivotal player in cytokine-induced beta cell damage. From a therapeutic standpoint, strategies aimed at targeting the activation of iNOS may harbor therapeutic potential in preserving beta cell survival in the face of proinflammatory cytokine exposure.
McCabe
Cillian
C
Regenerative Medicine Institute, National Centre for Biomedical Engineering Sciences, National University of Ireland, Galway, Ireland. cillianmccabe@gmail.com
Samali
Afshin
A
O'brien
Timothy
T
D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000008:administration & dosage*; D019610:Cytoprotection / Q000502:physiology*; D020672:I-kappa B Proteins / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D000072000:NF-KappaB Inhibitor alpha; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*
D016207:Cytokines; D020672:I-kappa B Proteins; C000606206:Nfkbia protein, rat; D017382:Reactive Oxygen Species; D000072000:NF-KappaB Inhibitor alpha; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat