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Title

Low concentration of interleukin-1beta induces FLICE-inhibitory protein-mediated beta-cell proliferation in human pancreatic islets

Authors
Maedler, Kathrin
Schumann, Desiree M
Sauter, Nadine
Ellingsgaard, Helga
Iwakura, Yoichiro
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Published in Diabetes. 2006, vol. 55, no. 10, p. 2713-22
Abstract High glucose concentrations have a dual effect on beta-cell turnover, inducing proliferation in the short-term and apoptosis in the long-term. Hyperglycemia leads to beta-cell production of interleuking (IL)-1beta in human pancreatic islets. Fas, a death receptor regulated by IL-1beta, is involved in glucose-induced beta-cell apoptosis. Fas engagement can be switched from death signal to induction of proliferation when the caspase 8 inhibitor, FLICE-inhibitory protein (FLIP), is active. Here, we show that IL-1beta at low concentrations may participate in the mitogenic actions of glucose through the Fas-FLIP pathway. Thus, exposure of human islets to low IL-1beta concentrations (0.01-0.02 ng/ml) stimulated proliferation and decreased apoptosis, whereas increasing amounts of IL-1beta (2-5 ng/ml) had the reverse effects. A similarly bimodal induction of FLIP, pancreatic duodenal homeobox (PDX)-1, and Pax4 mRNA expression, as well as glucose-stimulated insulin secretion, was observed. In contrast, Fas induction by IL-1beta was monophasic. Low IL-1beta also induced the IL-1 receptor antagonist (IL-1Ra), suppression of which by RNA interference abrogated the beneficial effects of low IL-1beta. The Fas antagonistic antibody ZB4 and small interfering RNA to FLIP prevented low IL-1beta-stimulated beta-cell proliferation. Consistent with our in vitro results, IL-1beta knockout mice displayed glucose intolerance along with a decrease in islet Fas, FLIP, Pax4, and PDX-1 transcripts. These findings indicate that low IL-1beta levels positively influence beta-cell function and turnover through the Fas-FLIP pathway and that IL-1Ra production prevents harmful effects of high IL-1beta concentrations.
Keywords AnimalsCASP8 and FADD-Like Apoptosis Regulating ProteinCell Proliferation/drug effectsGlucose Intolerance/physiopathologyHomeodomain Proteins/physiologyHumansInsulin-Secreting Cells/cytologyInterleukin 1 Receptor Antagonist ProteinInterleukin-1/physiologyIntracellular Signaling Peptides and Proteins/physiologyIslets of Langerhans/cytologyMiceOrgan Culture TechniquesPaired Box Transcription Factors/physiologySialoglycoproteins/physiologySignal Transduction/physiologyTrans-Activators/physiology
Identifiers
PMID: 17003335
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Research groups Chirurgie viscérale (104)
Cultures cellulaires et transplantations (519)
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MAEDLER, Kathrin et al. Low concentration of interleukin-1beta induces FLICE-inhibitory protein-mediated beta-cell proliferation in human pancreatic islets. In: Diabetes, 2006, vol. 55, n° 10, p. 2713-22. https://archive-ouverte.unige.ch/unige:34523

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Deposited on : 2014-02-28

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