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Low Concentration of Interleukin-1ß Induces FLICE-Inhibitory Protein–Mediated ß-Cell Proliferation in Human Pancreatic Islets

¹ Larry L. Hillblom Islet Research Center, University of California, Los Angeles, California
² Division of Endocrinology and Diabetes and Center for Integrative Human Physiology, University Hospital Zurich, Zurich, Switzerland
³ Department of Surgery, University Medical Center, Geneva, Switzerland
⁴ Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan
⁵ Division of Transplantation, University of Illinois at Chicago, Chicago, Illinois
⁶ Department of Cell Physiology and Metabolism, University Medical Center, Geneva, Switzerland

Address correspondence and reprint requests to Marc Y. Donath, MD, Division of Endocrinology and Diabetes, Department of Medicine, University Hospital, CH-8091 Zurich, Switzerland. E-mail: marc.donath{at}usz.ch

Abbreviations: FLIP, FLICE-inhibitory protein; GSIS, glucose-stimulated insulin secretion; IL, interleukin; IL-1Ra, IL-1 receptor antagonist; IRS, insulin receptor substrate; KRBB, Krebs-Ringer bicarbonate buffer; PDX, pancreatic duodenal homeobox; rh, recombinant human; siFLIP, siRNA directed to FLIP; siIL-1Ra, siRNA directed to IL-1Ra; siRNA, small interfering RNA; TUNEL, transferase-mediated dUTP nick-end labeling

High glucose concentrations have a dual effect on ß-cell turnover, inducing proliferation in the short-term and apoptosis in the long-term. Hyperglycemia leads to ß-cell production of interleuking (IL)-1ß in human pancreatic islets. Fas, a death receptor regulated by IL-1ß, is involved in glucose-induced ß-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-1ß at low concentrations may participate in the mitogenic actions of glucose through the Fas-FLIP pathway. Thus, exposure of human islets to low IL-1ß concentrations (0.01–0.02 ng/ml) stimulated proliferation and decreased apoptosis, whereas increasing amounts of IL-1ß (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-1ß was monophasic. Low IL-1ß also induced the IL-1 receptor antagonist (IL-1Ra), suppression of which by RNA interference abrogated the beneficial effects of low IL-1ß. The Fas antagonistic antibody ZB4 and small interfering RNA to FLIP prevented low IL-1ß–stimulated ß-cell proliferation. Consistent with our in vitro results, IL-1ß knockout mice displayed glucose intolerance along with a decrease in islet Fas, FLIP, Pax4, and PDX-1 transcripts. These findings indicate that low IL-1ß levels positively influence ß-cell function and turnover through the Fas-FLIP pathway and that IL-1Ra production prevents harmful effects of high IL-1ß concentrations.

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