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A High-content In Vitro Pancreatic Islet β-cell Replication Discovery Platform
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Production and function of IL-12 in islets and beta cells.

D A Taylor-Fishwick1, J R Weaver, W Grzesik

  • 1Strelitz Diabetes Center, Department of Internal Medicine, Eastern Virginia Medical School, 700 W. Olney Road, Norfolk, VA 23501, USA. Taylord@evms.edu

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|October 12, 2012
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Interleukin-12 (IL-12) directly impairs beta cell function and insulin secretion in diabetes. Beta cells produce IL-12, contributing to their own pathology in inflammatory conditions.

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Area of Science:

  • Immunology
  • Endocrinology
  • Cell Biology

Background:

  • Interleukin-12 (IL-12) is crucial in early inflammatory responses and implicated in diabetes pathogenesis.
  • The direct impact of IL-12 on pancreatic islets and beta cells remains largely uncharacterized.

Purpose of the Study:

  • To investigate the direct effects of IL-12 on human islet and beta cell function, gene expression, and protein production.
  • To determine if beta cells are a source of IL-12 and if IL-12 contributes to beta cell pathology.

Main Methods:

  • Primary human islets and murine beta cell lines (INS-1) were stimulated with IL-12 or a pro-inflammatory cytokine cocktail.
  • Assessed beta cell function, gene expression (including IFNG), and protein production.
  • Utilized IL-12 neutralizing antibodies to block IL-12 activity.

Main Results:

  • Pro-inflammatory cytokines induced islet dysfunction and increased IL-12 ligand and receptor expression in human islets.
  • IL-12 receptor localized to insulin-producing cells; IL-12 upregulated IFNG gene expression in INS-1 cells.
  • IL-12 impaired glucose-stimulated insulin secretion (GSIS) in both cell types; IL-12 blockade reversed pro-inflammatory cytokine-induced beta cell dysfunction.

Conclusions:

  • Beta cells are identified as a local source of IL-12 ligand.
  • IL-12 plays a direct role in mediating beta cell pathology, impacting insulin secretion and survival.