Document Detail


Extracellular factors and immunosuppressive drugs influencing insulin secretion of murine islets.
MedLine Citation:
PMID:  23039895     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Approximately 60% of transplanted islets undergo apoptosis within the first week post-transplantation into the liver attributed to poor engraftment, immune rejection and toxicity of immunosuppressive drugs. Understanding how extracellular matrix (ECM) components, immunosuppressive drugs and proinflammatory cytokines affect insulin secretion will contribute to an improved clinical outcome of islet transplantations. In this study, functional activity of isolated murine islets was measured by glucose-stimulated insulin secretion (GSIS) and by electrophysiological measurements using patch-clamp. Cultivating islets with soluble fibronectin or laminin, as opposed to with coated laminin, markedly increased GSIS. Addition of cyclosporin A reduced GSIS and suppressed glucose-induced spike activity. Tacrolimus affected neither GSIS nor spike activity, indicating a different mechanism. To evaluate the influence of proinflammatory cytokines, islets were incubated with interleukin (IL)-1β, tumour necrosis factor (TNF)-α or with supernatants from cultured Kupffer cells, the main mediators of inflammation in the hepatic sinusoids. IL-1β exerted a bimodal effect on insulin secretion, stimulating below 2 ng/ml and suppressing above 10 ng/ml. Soluble laminin in combination with a stimulatory IL-1β concentration further increased insulin secretion by 20% compared to IL-1β alone, while with high IL-1β concentrations soluble laminin slightly attenuated GSIS inhibition. TNF-α alone did not affect GSIS, but with stimulatory IL-1β concentrations completely abolished it. Similarly, supernatants derived from Kupffer cells exerted a bimodal effect on GSIS. Our data suggest that improved insulin secretion of transplanted islets could be achieved by including soluble laminin and low IL-1β concentrations in the islet cultivation medium, and by a simultaneous inhibition of cytokine secretion from Kupffer cells.
Authors:
V J Auer; E Janas; V Ninichuk; E Eppler; T S Weiss; S Kirchner; A M Otto; M J Stangl
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Clinical and experimental immunology     Volume:  170     ISSN:  1365-2249     ISO Abbreviation:  Clin. Exp. Immunol.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-10-08     Completed Date:  2013-03-18     Revised Date:  2013-11-05    
Medline Journal Info:
Nlm Unique ID:  0057202     Medline TA:  Clin Exp Immunol     Country:  England    
Other Details:
Languages:  eng     Pagination:  238-47     Citation Subset:  IM    
Copyright Information:
© 2012 The Authors. Clinical and Experimental Immunology © 2012 British Society for Immunology.
Affiliation:
Institute of Medical Engineering, Technische Universität München (IMETUM), Garching Center for Liver Cell Research, Department of Pediatrics and Adolescent Medicine, University of Regensburg Hospital Hepacult GmbH, Biopark Regensburg, Regensburg, Switzerland. veronika.auer@mytum.de
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MeSH Terms
Descriptor/Qualifier:
Animals
Apoptosis / drug effects
Cyclosporine / pharmacology
Extracellular Matrix / drug effects,  metabolism*,  physiology
Fibronectins / pharmacology
Glucose / metabolism
Humans
Immunosuppressive Agents / pharmacology*
Inflammation / metabolism
Insulin / metabolism,  secretion*
Interleukin-1beta / pharmacology
Islets of Langerhans / drug effects*,  metabolism,  physiology*,  secretion
Islets of Langerhans Transplantation
Kupffer Cells / metabolism
Laminin / pharmacology
Mice
Mice, Inbred C57BL
Tacrolimus / pharmacology
Tumor Necrosis Factor-alpha / metabolism
Chemical
Reg. No./Substance:
0/Fibronectins; 0/Immunosuppressive Agents; 0/Insulin; 0/Interleukin-1beta; 0/Laminin; 0/Tumor Necrosis Factor-alpha; 109581-93-3/Tacrolimus; 50-99-7/Glucose; 59865-13-3/Cyclosporine
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