Low concentration of interleukin-1beta induces FLICE-inhibitory protein-mediated beta-cell proliferation in human pancreatic islets
Authors: Benoit R Gauthier
Claes B Wollheim
Kathrin Maedler
Marc Y Donath
Reto Baertschiger
Helga Ellingsgaard
Desiree M Schumann
José Oberholzer
Domenico Bosco
Yoichiro Iwakura
Nadine Sauter
Journal: Diabetes (2006)
Discipline: CLINICAL MEDICINE
Keywords: High glucose concentrations; beta-cell turnover; proliferation; apoptosis; hyperglycemia
Affiliations: Larry L. Hillblom Islet Research Center, University of California, Los Angeles, CA, USA.

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. 

Retracted: No

PubPeer comments:
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 Please copy the left u201ctubulinu201c panel of Fig. 1E, Ardestani et al., J Biol Chem. 2011;286(19):17144-55 (published on March 10, 2011 as Manuscript M110.210526) and paste it into e.g. a photoshop, key note or power point document. The full blot belonging to this slice will appear. Bands 3-6 of the full slice represent the u201etubulinu201c bands given in the paper (follow the green lines) but apparently bands of the full slice show significant similarities to figures shown in earlier papers of the group as well including the present paper. The panel from this paper is indicated by dotted red lines. ![file] , 
 2018 update to expression of concern. http: diabetes.diabetesjournals.org content early 2018 09 11 db18-ec2018b.long , 
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 2020 retraction. https: diabetes.diabetesjournals.org content early 2020 01 08 db20-rt03a Statement of Retraction. Kathrin Maedler, Desiree M. Schumann, Nadine Sauter, Helga Ellingsgaard, Domenico Bosco, Reto Baertschiger, Yoichiro Iwakura, Josu00e9 Oberholzer, Claes B. Wollheim, Benoit R. Gauthier, and Marc Y. Donath. Low Concentration of Interleukin-1b Induces FLICE-Inhibitory Proteinu2013Mediated b-Cell Proliferation in Human Pancreatic Islets. Diabetes 2006;55:2713u20132722. DOI:10.2337 db05-1430. PMID: 17003335 American Diabetes Association https: doi.org 10.2337 db20-rt03a The above-cited article has been retracted by the American Diabetes Association (ADA), the publisher of Diabetes. This article was previously the subject of an expression of concern in August 2016 (Diabetes 2016;65:2462. DOI: 10.2337 db16-ec08a. PMID: 27456623). An updated amendment to this article was also published in November 2018 (Diabetes 2018;67:2479u20132480. DOI: 10.2337 db18-ec2018b. PMID: 30213822). In September 2018, ADAu2019s Panel on Ethical Scientific Programs (ESP) contacted the University of Zurich, the lead and corresponding authorsu2019 institution at the time the research was conducted, to request an institutional investigation into the possible duplication of several images presented in this article. The Universityu2019s review is ongoing. The ESP has since coordinated an independent review of the issues described in the amendments. On the basis of its review, the ESP has determined that the following instances of image duplication compromise the overall reliability of the study. u0001 In a 2009 PLOS ONE article (PLoS ONE 2009;4:e4394. DOI: 10.1371 journal.pone .0004394), lanes 1 and 2 of the u201cb-Actinu201d panel in Fig. 1A appear to be the same as lanes 2 and 3 of the u201cActin 42 kDau201d panel in Fig. 3G of this article. It should be noted that a correction to replace Fig. 1A in the PLOS ONE article was published in May 2015 (PLoS ONE 2015;10:e0117766. DOI: 10.1371 journal.pone.0117766). u0001 Lane 4 of the PDX1 panel in Fig. 1E of a 2011 article in the Journal of Biological Chemistry (J Biol Chem 2011;286:17144u201317155. DOI: 10.1074 jbc.M110.210526) closely resembles lane 1 of the FLIP 55KDa panel of Fig. 3D of this 2006 Diabetes article. In addition, lane 8 of the PDX1 panel of Fig. 1E of the Journal of Biological Chemistry article closely resembles lane 5 of the FLIP 55KDa panel in Fig. 3D of this Diabetes article. The Journal of Biological Chemistry article was retracted in November 2015 (DOI: 10.1074 jbc.A110.210526). u0001 Lanes 2, 4, and 6 of the u201cActin 42 kDau201d panel of Fig. 3D appear to be duplicates. u0001 Lanes 3u20136 of the u201cActin 42 kDAu201d strip of Fig. 3B of this article and lanes 3u20136 of the u201cActin, 96 hu201d strip in Fig. 3D of Diabetes 55:2455u20132462, with horizontal rotation and contrast and size adjustments, appear to be duplicates. ADA, as the publisher of Diabetes, has chosen to retract this publication upon the recommendation of the ESP. Information about ADAu2019s review poli ,