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

Susan J. Burke, Danhong Lu, Tim E. Sparer, Michael Karlstad, J. Jason Collier

Research output: Contribution to journalArticle

12 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)54-62
Number of pages9
JournalMolecular Immunology
Volume62
Issue number1
DOIs
StatePublished - Jan 1 2014

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Interleukin-1
Islets of Langerhans
Cell Line
Genes
Histone Code
Inflammation Mediators
Islets of Langerhans Transplantation
Messenger RNA
Proteins
RNA Polymerase II
Chemokines
Diabetes Mellitus
Neutrophils
Phosphotransferases
Cytokines
Inflammation

All Science Journal Classification (ASJC) codes

  • Immunology
  • Molecular Biology

Cite this

Transcription of the gene encoding TNF-α is increased by IL-1β in rat and human islets and β-cell lines. / Burke, Susan J.; Lu, Danhong; Sparer, Tim E.; Karlstad, Michael; Collier, J. Jason.

In: Molecular Immunology, Vol. 62, No. 1, 01.01.2014, p. 54-62.

Research output: Contribution to journalArticle

Burke, Susan J. ; Lu, Danhong ; Sparer, Tim E. ; Karlstad, Michael ; Collier, J. Jason. / Transcription of the gene encoding TNF-α is increased by IL-1β in rat and human islets and β-cell lines. In: Molecular Immunology. 2014 ; Vol. 62, No. 1. pp. 54-62.
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