title: Uncoupling protein-2 increases nitric oxide production and TNFAIP3 pathway activation in pancreatic islets.
abstract: Mutations in the uncoupling protein 2 (Ucp2) gene are linked to type-2 diabetes. Here, a potential mechanism by which lack of UCP2 is cytoprotective in pancreatic β-cells was investigated. Nitric oxide (NO) production was elevated in Ucp2(-/-) islets. Proliferation (cyclin D2, Ccnd2) and anti-apoptosis (Tnfaip3) genes had increased expression in Ucp2(-/-) islets, whereas the mRNA of pro-apoptosis genes (Jun, Myc) was reduced. TNFAIP3 cellular localization was detected in both α- and β-cells of Ucp2(-/-) islets but in neither α- nor β-cells of UCP2(+)(/)(+) islets, where it was detected in pancreatic polypeptide-expressing cells. TNFAIP3 distribution was not markedly altered 14 days after streptozotocin treatment. Basal apoptosis was attenuated in Ucp2(-/-) β-cells, while the nuclear factor κB (NF-κB) pathway was transactivated after islet isolation. Ucp2(+/+) and Ucp2(-/-) islets were treated with cytokines for 24 h. Cytokines did not increase NF-κB transactivation or apoptosis in Ucp2(-/-) islets and TNFAIP3 was more strongly induced in Ucp2(-/-) islets. Inhibition of NO production strongly reduced NF-κB activation and apoptosis. These data show that null expression of Ucp2 induces transactivation of NF-κB in isolated islets, possibly due to NO-dependent up-regulation of inhibitor of κB kinase β activity. NF-κB transactivation appears to result in altered expression of genes that enhance a pro-survival phenotype basally and when β-cells are exposed to cytokines. TNFAIP3 is of particular interest because of its ability to regulate NF-κB signaling pathways.
authors.affiliation: Department of Biomedical Sciences, University of Prince Edward Island, Charlottetown, Prince Edward Island, Canada C1A 4P3.
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Niño Fong
authors.forename: Zahra
authors.initials: Z
authors.lastname: Fatehi-Hassanabad
authors.forename: Simon C
authors.initials: SC
authors.lastname: Lee
authors.forename: Hongfang
authors.initials: H
authors.lastname: Lu
authors.forename: Michael B
authors.initials: MB
authors.lastname: Wheeler
authors.forename: Catherine B
authors.initials: CB
authors.lastname: Chan
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D015153:Blotting, Western; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism*; D051379:Mice; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis*; D016133:Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D000071246:Uncoupling Protein 2
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D007473:Ion Channels; D024101:Mitochondrial Proteins; D016328:NF-kappa B; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2; D009569:Nitric Oxide; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D003546:Cysteine Endopeptidases; C513261:Tnfaip3 protein, mouse