Leptin Modulates β Cell Expression of IL-1 Receptor Antagonist and Release of IL-1β in Human Islets

High concentrations of glucose induce β cell production of IL-1β, leading to impaired β cell function and apoptosis in human pancreatic islets. IL-1 receptor antagonist (IL-1Ra) is a naturally occurring antagonist of IL-1β and protects cultured human islets from glucotoxicity. Therefore, the balance...

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Bibliographic Details
Published in:	Proceedings of the National Academy of Sciences - PNAS Vol. 101; no. 21; pp. 8138 - 8143
Main Authors:	Maedler, Kathrin, Sergeev, Pavel, Ehses, Jan A., Mathe, Zoltan, Bosco, Domenico, Berney, Thierry, Dayer, Jean-Michel, Reinecke, Manfred, Halban, Philippe A., Donath, Marc Y., Unger, Roger H.
Format:	Journal Article
Language:	English
Published:	National Academy of Sciences 25-05-2004 National Acad Sciences
Subjects:	Adipocytes Apoptosis B lymphocytes Biological Sciences Cellular immunity Cultured cells Diabetes Insulin Physical Sciences Small interfering RNA Type 1 diabetes mellitus Type 2 diabetes mellitus
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Summary:	High concentrations of glucose induce β cell production of IL-1β, leading to impaired β cell function and apoptosis in human pancreatic islets. IL-1 receptor antagonist (IL-1Ra) is a naturally occurring antagonist of IL-1β and protects cultured human islets from glucotoxicity. Therefore, the balance of IL-1β and IL-1Ra may play a crucial role in the pathogenesis of diabetes. In the present study, we observed expression of IL-1Ra in human pancreatic β cells of nondiabetic individuals, which was decreased in tissue sections of type 2 diabetic patients. In vitro, chronic exposure of human islets to leptin, a hormone secreted by adipocytes, decreased β cell production of IL-1Ra and induced IL-1β release from the islet preparation, leading to impaired β cell function, caspase-3 activation, and apoptosis. Exogenous addition of IL-1Ra protected cultured human islets from the deleterious effects of leptin. Antagonizing IL-1Ra by introduction of small interfering RNA to IL-1Ra into human islets led to caspase-3 activation, DNA fragmentation, and impaired β cell function. Moreover, siIL-1Ra enhanced glucose-induced β cell apoptosis. These findings demonstrate expression of IL-1Ra in the human β cell, providing localized protection against leptin- and glucose-induced islet IL-1β.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 This paper was submitted directly (Track II) to the PNAS office. Edited by Roger H. Unger, University of Texas Southwestern Medical Center, Dallas, TX, and approved March 16, 2004 Abbreviations: FFA, free fatty acid; IL-1Ra, IL-1 receptor antagonist; rh IL-1Ra, recombinant human IL-1Ra; siRNA, small interfering RNA; TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling; siIL-1Ra, siRNA to IL-1Ra; ERK, extracellular signal-regulated kinase; JAK, Janus tyrosine kinase; STAT, signal transducers and activators of transcription. To whom correspondence should be addressed. E-mail: marc.donath@usz.ch.
ISSN:	0027-8424 1091-6490
DOI:	10.1073/pnas.0305683101