Document Detail


Production and function of IL-12 in islets and beta cells.
MedLine Citation:
PMID:  23052055     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
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:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2012-10-03
Journal Detail:
Title:  Diabetologia     Volume:  56     ISSN:  1432-0428     ISO Abbreviation:  Diabetologia     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2012-12-18     Completed Date:  2013-05-28     Revised Date:  2014-01-09    
Medline Journal Info:
Nlm Unique ID:  0006777     Medline TA:  Diabetologia     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  126-35     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Antibodies, Neutralizing / metabolism
Cell Line
Cell Membrane / metabolism
Cytokines / metabolism
Diabetes Mellitus, Type 2 / immunology,  metabolism*
Gene Expression Regulation*
Humans
Insulin / secretion
Insulin-Secreting Cells / immunology,  metabolism*,  secretion
Interferon-gamma / metabolism
Interleukin-12 / antagonists & inhibitors,  biosynthesis*,  metabolism
Islets of Langerhans / immunology,  metabolism*,  secretion
Mice
RNA, Messenger / metabolism
Receptors, Interleukin-12 / metabolism*
Signal Transduction*
Surface Properties
Tissue Culture Techniques
Tissue Donors
Grant Support
ID/Acronym/Agency:
DK090490/DK/NIDDK NIH HHS; HL112605/HL/NHLBI NIH HHS; R01 DK090490/DK/NIDDK NIH HHS; R01 HL112605/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Antibodies, Neutralizing; 0/Cytokines; 0/IFNG protein, human; 0/Insulin; 0/RNA, Messenger; 0/Receptors, Interleukin-12; 187348-17-0/Interleukin-12; 82115-62-6/Interferon-gamma
Comments/Corrections

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