Transcription of the gene encoding TNF-α is increased by IL-1β in rat and human islets and β-cell lines

Synthesis and secretion of immunomodulatory proteins, such as cytokines and chemokines, controls the inflammatory response within pancreatic islets. When this inflammation does not resolve, destruction of pancreatic islet beta-cells leads to diabetes mellitus. Production of the soluble mediators of inflammation, such as TNF-alpha and IL-1 beta, from resident and invading immune cells, as well as directly from islet beta-cells, is also associated with suboptimal islet transplantation outcomes. In this study, we found that IL-1 beta induces rapid increases in TNF-alpha mRNA in rat and human islets and the 832/13 clonal beta-cell line. The surge in transcription of the TNF-alpha gene required the inhibitor of kappa B kinase beta (I kappa K beta), the p65 subunit of the NF-kappa B and a signal-specific recruitment of RNA polymerase II to the gene promoter. Of note was the increased intracellular production of TNF-alpha protein in a manner consistent with mRNA accumulation in response to IL-1 beta, but no detectable secretion of TNF-alpha into the media. Additionally, TNF-alpha specifically induces expression of CD11b, but not CD11c, on neutrophils, which could contribute to the inflammatory milieu and diabetes progression. We conclude that activation of the NF-kappa B pathway in pancreatic beta-cells leads to rapid intracellular production of the pro-inflammatory TNF-alpha protein through a combination of specific histone covalent modifications and NF-kappa B signaling pathways. (C) 2014 Elsevier Ltd. All rights reserved.