title: Transcription of the gene encoding TNF-α is increased by IL-1β in rat and human islets and β-cell lines.
abstract: 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 β-cells leads to diabetes mellitus. Production of the soluble mediators of inflammation, such as TNF-α and IL-1β, from resident and invading immune cells, as well as directly from islet β-cells, is also associated with suboptimal islet transplantation outcomes. In this study, we found that IL-1β induces rapid increases in TNF-α mRNA in rat and human islets and the 832/13 clonal β-cell line. The surge in transcription of the TNF-α gene required the inhibitor of kappa B kinase beta (IκKβ), the p65 subunit of the NF-κB and a signal-specific recruitment of RNA polymerase II to the gene promoter. Of note was the increased intracellular production of TNF-α protein in a manner consistent with mRNA accumulation in response to IL-1β, but no detectable secretion of TNF-α into the media. Additionally, TNF-α 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-κB pathway in pancreatic β-cells leads to rapid intracellular production of the pro-inflammatory TNF-α protein through a combination of specific histone covalent modifications and NF-κB signaling pathways.
authors: Laboratory of Islet Biology and Inflammation, Pennington Biomedical Research Center, Baton Rouge, LA 70808, United States.
authors: Susan J
authors: SJ
authors: Burke
authors: Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC 27704, United States.
authors: Danhong
authors: D
authors: Lu
authors: Department of Microbiology, University of Tennessee, Knoxville, TN 37996, United States.
authors: Tim E
authors: TE
authors: Sparer
authors: Department of Surgery, Graduate School of Medicine, University of Tennessee Medical Center, Knoxville, TN 37920, United States.
authors: Michael D
authors: MD
authors: Karlstad
authors: Laboratory of Islet Biology and Inflammation, Pennington Biomedical Research Center, Baton Rouge, LA 70808, United States. Electronic address: Jason.collier@pbrc.edu.
authors: J Jason
authors: JJ
authors: Collier
mesh_terms: D000818:Animals; D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000276:immunology*; D053583:Interleukin-1beta / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism
chemical_list: D053583:Interleukin-1beta; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D051550:I-kappa B Kinase
keywords: Cytokine; Diabetes mellitus; Inflammation; Islet; NF-κB; Transcription