PNNL

Abstract

Type 1 diabetes (T1D) results from the autoimmune destruction of the insulin-producing ß cells of the pancreas. Omega-3 fatty acids protect ß cells and reduce the incidence of T1D, but the mechanism is poorly understood. We have shown that omega-3 fatty acids reduce pro-inflammatory cytokine-mediated ß-cell apoptosis by upregulating the expression of the ADP-ribosylhydrolase ARH3. Here, we further investigate the ß-cell protection mechanism of ARH3 by performing siRNA analysis of its gene Adprhl2 in MIN6 insulin-producing cells, subsequent treatment with a cocktail of the pro-inflammatory cytokines IL-1ß + IFN-? + TNF-a, followed by proteomics analysis. ARH3 regulated proteins from several pathways related to the nucleus (splicing, RNA surveillance, and nucleocytoplasmic transport), mitochondria (metabolic pathways), and endoplasmic reticulum (protein folding). ARH3 also regulated the levels of proteins related to antigen processing and presentation, and the chemokine-signaling pathway. We further studied the role of ARH in regulating the chemokine CXCL9. We confirmed that ARH3 reduces the cytokine-induced expression of CXCL9 by ELISA. CXCL9 expression was also regulated by omega-3 fatty acids. In conclusion, we demonstrate that omega-3 fatty acids regulate CXCL9 expression via ARH3, which may have a role in protecting ß cells from immune attack thereby preventing T1D development.