| Production and function of IL-12 in islets and beta cells. | |
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MedLine Citation:
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PMID: 23052055 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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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. |
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Authors:
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D A Taylor-Fishwick; J R Weaver; W Grzesik; S Chakrabarti; S Green-Mitchell; Y Imai; N Kuhn; J L Nadler |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-10-3 |
Journal Detail:
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Title: Diabetologia Volume: - ISSN: 1432-0428 ISO Abbreviation: Diabetologia Publication Date: 2012 Oct |
Date Detail:
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Created Date: 2012-10-11 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0006777 Medline TA: Diabetologia Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Strelitz 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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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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