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

Low Concentration of Interleukin-1β Induces FLICE-Inhibitory Protein–Mediated β-Cell Proliferation in Human Pancreatic Islets Kathrin Maedler 1 , Desiree M. Schumann 2 , Nadine Sauter 2 , Helga Ellingsgaard 2 , Domenico Bosco 3 , Reto Baertschiger 3 , Yoichiro Iwakura 4 , José Oberholzer 5 , Claes B. Wollheim 6 , Benoit R. Gauthier 6 and Marc Y. Donath 2 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 Abstract High glucose concentrations have a dual effect on β-cell turnover, inducing proliferation in the short-term and apoptosis in the long-term. Hyperglycemia leads to β-cell production of interleuking (IL)-1β in human pancreatic islets. Fas, a death receptor regulated by IL-1β, is involved in glucose-induced β-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-1β at low concentrations may participate in the mitogenic actions of glucose through the Fas-FLIP pathway. Thus, exposure of human islets to low IL-1β concentrations (0.01–0.02 ng/ml) stimulated proliferation and decreased apoptosis, whereas increasing amounts of IL-1β (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-1β was monophasic. Low IL-1β also induced the IL-1 receptor antagonist (IL-1Ra), suppression of which by RNA interference abrogated the beneficial effects of low IL-1β. The Fas antagonistic antibody ZB4 and small interfering RNA to FLIP prevented low IL-1β–stimulated β-cell proliferation. Consistent with our in vitro results, IL-1β knocko