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.