Identification of novel cytokine-induced genes in pancreatic beta-cells byhigh-density oligonucleotide arrays

Type 1 diabetes is an autoimmune disease resulting from the selective destr uction of insulin-producing beta -cells. Cytokines may contribute to pancre atic beta -cell death in type 1 diabetes. beta -cell exposure to interleuki n (IL)-1 beta induces functional impairment, whereas beta -cell culture for 6-9 days in the presence of IL-1 beta and interferon (INF)-gamma leads to apoptosis. To clarify the mechanisms involved in these effects of cytokines , we studied the general pattern of cytokine-induced gene expression in bet a -cells. Primary rat beta -cells were fluorescence-activated cell sorter-p urified and exposed for 6 or 24 h to control condition, IL-1 beta + INF-gam ma, or IL-1 beta alone (24 h only). Gene expression profile was analyzed in duplicate by oligonucleotide arrays. Nearly 3,000 transcripts were detecte d in controls and cytokine-treated beta -cells. Of these, 96 and 147 displa yed changes in expression after 6 and 24 h, respectively, of exposure to IL -1 beta + INF-gamma, whereas 105 transcripts were modified after a 24-h exp osure to IL-1 beta. The cytokine-responsive genes were clustered according to their biological functions. The major clusters observed were metabolism, signal transduction, transcription factors, protein synthesis/processing, hormones, and related receptors. These modifications in gene expression may explain some of the cytokine effects in beta -cells, such as decreased pro tein biosynthesis and insulin release. In addition, there was induction of diverse cytokines and chemokines; this suggests that beta -cells may contri bute to mononuclear cell homing during insulitis. Several of the cytokine-i nduced genes are potentially regulated by the transcription factor NF-kappa B. Clarification of the function of the identified cytokine-induced gene pa tterns may unveil some of the mechanisms involved in beta -cell damage and repair in type 1 diabetes.