title: Cytokine-mediated β-cell damage in PARP-1-deficient islets.
abstract: Poly(ADP)-ribose polymerase (PARP) is an abundant nuclear protein that is activated by DNA damage; once active, it modifies nuclear proteins through attachment of poly(ADP)-ribose units derived from β-nicotinamide adenine dinucleotide (NAD(+)). In mice, the deletion of PARP-1 attenuates tissue injury in a number of animal models of human disease, including streptozotocin-induced diabetes. Also, inflammatory cell signaling and inflammatory gene expression are attenuated in macrophages isolated from endotoxin-treated PARP-1-deficient mice. In this study, the effects of PARP-1 deletion on cytokine-mediated β-cell damage and macrophage activation were evaluated. There are no defects in inflammatory mediator signaling or inflammatory gene expression in macrophages and islets isolated from PARP-1-deficient mice. While PARP-1 deficiency protects islets against cytokine-induced islet cell death as measured by biochemical assays of membrane polarization, the genetic absence of PARP-1 does not effect cytokine-induced inhibition of insulin secretion or cytokine-induced DNA damage in islets. While PARP-1 deficiency appears to provide protection from cell death, it fails to provide protection against the inhibitory actions of cytokines on insulin secretion or the damaging actions on islet DNA integrity.
authors.affiliation: Department of Pediatrics, Saint Louis University, St. Louis, MO, USA. andreone@slu.edu
authors.forename: Teresa
authors.initials: T
authors.lastname: Andreone
authors.forename: Gordon P
authors.initials: GP
authors.lastname: Meares
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Hughes
authors.forename: Polly A
authors.initials: PA
authors.lastname: Hansen
authors.forename: John A
authors.initials: JA
authors.lastname: Corbett
mesh_terms: D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D004249:DNA Damage; D005260:Female; D017353:Gene Deletion; D015870:Gene Expression; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008262:Macrophage Activation; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials; D051379:Mice; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D016207:Cytokines; D007328:Insulin; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases