title: Low concentration of interleukin-1beta induces FLICE-inhibitory protein-mediated beta-cell proliferation in human pancreatic islets.
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.
authors.affiliation: Larry L. Hillblom Islet Research Center, University of California, Los Angeles, CA, USA.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Maedler
authors.forename: Desiree M
authors.initials: DM
authors.lastname: Schumann
authors.forename: Nadine
authors.initials: N
authors.lastname: Sauter
authors.forename: Helga
authors.initials: H
authors.lastname: Ellingsgaard
authors.forename: Domenico
authors.initials: D
authors.lastname: Bosco
authors.forename: Reto
authors.initials: R
authors.lastname: Baertschiger
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.forename: José
authors.initials: J
authors.lastname: Oberholzer
authors.forename: Claes B
authors.initials: CB
authors.lastname: Wollheim
authors.forename: Benoit R
authors.initials: BR
authors.lastname: Gauthier
authors.forename: Marc Y
authors.initials: MY
authors.lastname: Donath
mesh_terms: D000818:Animals; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D049109:Cell Proliferation / Q000187:drug effects; D018149:Glucose Intolerance / Q000503:physiopathology; D018398:Homeodomain Proteins / Q000502:physiology; D006801:Humans; D050417:Insulin-Secreting Cells / Q000166:cytology*; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D007515:Islets of Langerhans / Q000166:cytology*; D051379:Mice; D009924:Organ Culture Techniques; D051761:Paired Box Transcription Factors / Q000502:physiology; D012795:Sialoglycoproteins / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D015534:Trans-Activators / Q000502:physiology
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; C506387:Cflar protein, mouse; D018398:Homeodomain Proteins; C507763:IL1RN protein, human; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D047908:Intracellular Signaling Peptides and Proteins; D051761:Paired Box Transcription Factors; C110218:Pax4 protein, mouse; D012795:Sialoglycoproteins; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein