Journal
MOLECULAR IMMUNOLOGY
Volume 62, Issue 1, Pages 54-62Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.molimm.2014.05.019
Keywords
Cytokine; Diabetes mellitus; Inflammation; Islet; NF-kappa beta; Transcription
Categories
Funding
- COBRE [NIH8 P20-GM103528]
- NORC center grants from the National Institutes of Health [NIH 1P30-DK072476]
- NIH [R01AI071042-01A2, P20-GM103528]
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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.
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