Low concentration of interleukin-1beta induces FLICE-inhibitory protein-mediated beta-cell proliferation in human pancreatic islets
| Autor: | Domenico Bosco, Reto M. Baertschiger, Yoichiro Iwakura, Jose Oberholzer, Benoit R. Gauthier, Claes B. Wollheim, Marc Y. Donath, Helga Ellingsgaard, Nadine S. Sauter, Desiree M. Schumann, Kathrin Maedler |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2006 |
| Předmět: |
medicine.medical_specialty
Small interfering RNA medicine.drug_class Sialoglycoproteins Endocrinology Diabetes and Metabolism CASP8 and FADD-Like Apoptosis Regulating Protein Biology Caspase 8 Cell Proliferation/drug effects Islets of Langerhans Glucose Intolerance/physiopathology Mice Insulin-Secreting Cells/cytology Organ Culture Techniques Insulin-Secreting Cells Internal medicine Glucose Intolerance Internal Medicine medicine Paired Box Transcription Factors Animals Humans Trans-Activators/physiology Receptor ddc:612 Cell Proliferation Paired Box Transcription Factors/physiology Homeodomain Proteins Intracellular Signaling Peptides and Proteins/physiology ddc:617 Signal Transduction/physiology Pancreatic islets Intracellular Signaling Peptides and Proteins Homeodomain Proteins/physiology Sialoglycoproteins/physiology Receptor antagonist Islets of Langerhans/cytology Interleukin 1 Receptor Antagonist Protein Endocrinology medicine.anatomical_structure Apoptosis Flip Trans-Activators PAX4 Interleukin-1/physiology Interleukin-1 Signal Transduction |
| Zdroj: | Diabetes, Vol. 55, No 10 (2006) pp. 2713-22 |
| ISSN: | 0012-1797 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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