Journal article
Production and function of IL-12 in islets and beta cells
Diabetologia, Vol.56(1), pp.126-135
2013
DOI: 10.1007/s00125-012-2732-9
PMCID: PMC3651896
PMID: 23052055
Abstract
Aims/hypothesis
IL-12 is an important cytokine in early inflammatory responses and is implicated in the immune-mediated pathogenesis of pancreatic islets in diabetes. However, little is known about the direct effects of IL-12 on islets and beta cells.
Methods
In this study, beta cell function, gene expression and protein production were assessed in primary human donor islets and murine beta cell lines in response to stimulation with IL-12 or a pro-inflammatory cytokine cocktail (TNF-α, IL-1β and IFN-γ).
Results
The pro-inflammatory cytokine cocktail induced islet dysfunction and potently increased the expression and production of IL-12 ligand and IL-12 receptor in human islets. In human islets, the receptor for IL-12 co-localised to the cell surface of insulin-producing cells. Both IL-12 ligand and IL-12 receptor are expressed in the homogeneous beta cell line INS-1. IL-12 induced changes in gene expression, including a dose-dependent upregulation of IFNγ (also known as IFNG), in INS-1 cells. A neutralising antibody to IL-12 directly inhibited IFNγ gene expression in human donor islets induced by either IL-12 or pro-inflammatory cytokine stimulation. Functionally, IL-12 impaired glucose-stimulated insulin secretion (GSIS) in INS-1 cells and human donor islets. A neutralising antibody to IL-12 reversed the beta cell dysfunction (uncoupling of GSIS or induction of caspase-3 activity) induced by pro-inflammatory cytokines.
Conclusions/interpretation
These data identify beta cells as a local source of IL-12 ligand and suggest a direct role of IL-12 in mediating beta cell pathology.
Details
- Title: Subtitle
- Production and function of IL-12 in islets and beta cells
- Creators
- D. A TAYLOR-FISHWICK - Strelitz Diabetes Center, Department of Internal Medicine, Eastern Virginia Medical School, 700 W. Olney Road, Norfolk, VA 23501, United StatesJ. R WEAVER - Strelitz Diabetes Center, Department of Internal Medicine, Eastern Virginia Medical School, 700 W. Olney Road, Norfolk, VA 23501, United StatesW GRZESIK - Strelitz Diabetes Center, Department of Internal Medicine, Eastern Virginia Medical School, 700 W. Olney Road, Norfolk, VA 23501, United StatesS CHAKRABARTI - Strelitz Diabetes Center, Department of Internal Medicine, Eastern Virginia Medical School, 700 W. Olney Road, Norfolk, VA 23501, United StatesS GREEN-MITCHELL - Strelitz Diabetes Center, Department of Internal Medicine, Eastern Virginia Medical School, 700 W. Olney Road, Norfolk, VA 23501, United StatesY IMAI - Strelitz Diabetes Center, Department of Internal Medicine, Eastern Virginia Medical School, 700 W. Olney Road, Norfolk, VA 23501, United StatesN KUHN - Strelitz Diabetes Center, Department of Internal Medicine, Eastern Virginia Medical School, 700 W. Olney Road, Norfolk, VA 23501, United StatesJ. L NADLER - Strelitz Diabetes Center, Department of Internal Medicine, Eastern Virginia Medical School, 700 W. Olney Road, Norfolk, VA 23501, United States
- Resource Type
- Journal article
- Publication Details
- Diabetologia, Vol.56(1), pp.126-135
- Publisher
- Springer
- DOI
- 10.1007/s00125-012-2732-9
- PMID
- 23052055
- PMCID
- PMC3651896
- ISSN
- 0012-186X
- eISSN
- 1432-0428
- Language
- English
- Date published
- 2013
- Academic Unit
- Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984094510602771
Metrics
13 Record Views