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

Maedler, Kathrin; Schumann, Desiree M.; Sauter, Nadine S.; Ellingsgaard, Helga; Bosco, Domenico; Baertschiger, Reto M.; Iwakura, Yoichiro; Oberholzer, José; Wollheim, Claes; Gauthier, Benoit R.; Donath, Marc Y.

doi:10.2337/db05-1430

Cited by 150 publications

(155 citation statements)

References 61 publications

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“…The balance between caspase-8 and its cellular regulator FLIP can switch Fas-mediated signalling to apoptosis or proliferation [49,50]. This raises the possibility that hIAPP aggregates, like elevated glucose, may reduce beta cell FLIP levels, thereby switching Fas signalling towards apoptosis.…”

Section: Discussionmentioning

confidence: 99%

The role of caspase-8 in amyloid-induced beta cell death in human and mouse islets

et al. 2014

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Aims/hypothesis Reduced beta cell mass due to increased beta cell apoptosis is a key defect in type 2 diabetes. Islet amyloid, formed by the aggregation of human islet amyloid polypeptide (hIAPP), contributes to beta cell death in type 2 diabetes and in islet grafts in patients with type 1 diabetes. In this study, we used human islets and hIAPP-expressing mouse islets with beta cell Casp8 deletion to (1) investigate the role of caspase-8 in amyloid-induced beta cell apoptosis and (2) test whether caspase-8 inhibition protects beta cells from amyloid toxicity. Methods Human islet cells were cultured with hIAPP alone, or with caspase-8, Fas or amyloid inhibitors. Human islets and wild-type or hIAPP-expressing mouse islets with or without caspase-8 expression (generated using a Cre/loxP system) were cultured to form amyloid. Caspase-8 and -3 activation, Fas and FLICE inhibitory protein (FLIP) expression, islet beta cell and amyloid area, IL-1β levels, and the beta:alpha cell ratio were assessed. Results hIAPP treatment induced activation of caspase-8 and -3 in islet beta cells (via Fas upregulation), resulting in apoptosis, which was markedly reduced by blocking caspase-8, Fas or amyloid. Amyloid formation in cultured human and hIAPP-expressing mouse islets induced caspase-8 activation, which was associated with Fas upregulation and elevated islet IL-1β levels. hIAPP-expressing mouse islets with Casp8 deletion had comparable amyloid, IL-1β and Fas levels with those expressing hIAPP and Casp8, but markedly lower beta cell apoptosis, higher beta:alpha cell ratio, greater beta cell area, and enhanced beta cell function. Conclusions/interpretation Beta cell Fas upregulation by endogenously produced and exogenously applied hIAPP aggregates promotes caspase-8 activation, resulting in beta cell apoptosis. The prevention of amyloid-induced caspase-8 activation enhances beta cell survival and function in islets.

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Section: Discussionmentioning

confidence: 99%

The role of caspase-8 in amyloid-induced beta cell death in human and mouse islets

et al. 2014

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“…However, a recent study analysing surgical samples from four gastrinoma patients showed no evidence of increased beta cell replication [15]. Increased beta cell replication has been noted in rodent studies involving overproduction of γ-interferon, transforming growth factor-β, IL-1β and other cytokines [16][17][18][19]. This finding has recently been supported by a study in which pancreatic specimens obtained from patients with chronic pancreatitis showed evidence of increased numbers of insulin-positive cells and cells containing transcriptional markers of endocrine origin (i.e.…”

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confidence: 95%

Pancreatic adenocarcinoma patients with localised chronic severe pancreatitis show an increased number of single beta cells, without alterations in fractional insulin area

et al. 2008

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Aims/hypothesis Recent histological analysis of pancreases obtained from patients with long-standing type 1 diabetes identified chronic islet inflammation and limited evidence suggestive of beta cell replication. Studies in rodent models also suggest that beta cell replication can be induced by certain inflammatory cytokines and by gastrin. We therefore tested the hypothesis that beta cell replication is observed in non-autoimmune human pancreatic disorders in which localised inflammation or elevated gastrin levels are present. Methods Resected operative pancreatic specimens were obtained from patients diagnosed with primary adenocarcinoma (with or without chronic severe pancreatitis) or gastrinoma. Additional pancreatic tissue was obtained from autopsy control patients. Immunohistochemistry was used to assess fractional insulin area, beta cell number and replication rate and differentiation factors relevant to beta cell development.Results Fractional insulin area was similar among groups. Patients with pancreatic adenocarcinoma and localised chronic severe pancreatitis displayed significant increases in the number of single beta cells, as well as increased beta cell replication rate and levels of neurogenic differentiation 1 in islets. Patients with gastrinoma demonstrated significant increases in the number of single beta cells, but the beta cell replication rate and islet differentiation factor levels were similar to those in the control group. Conclusions/interpretation These findings indicate that chronic severe pancreatic inflammation can be associated with significant effects on beta cell number or replication rate, depending on the distribution of the cells. This information may prove useful for attempts seeking to design therapies aimed at inducing beta cell replication as a means of reversing diabetes.

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“…Although high levels of IL-1␤ have been implicated in inflammatory diseases (3,8) including type 2 diabetes (9 -12), low levels have beneficial effects on pancreatic beta cell function, proliferation, and survival (13)(14)(15)(16), intestinal epithelial cell survival (17,18), and neuronal response to injury (19). As in many receptor-ligand systems, IL-1␤ signaling is complex, with multiple ligands interacting with membranebound and soluble forms of several receptors (20).…”

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confidence: 99%

Kinetic Approach to Pathway Attenuation Using XOMA 052, a Regulatory Therapeutic Antibody That Modulates Interleukin-1β Activity

Roell

Issafras

Bauer³

et al. 2010

Journal of Biological Chemistry

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Many therapeutic antibodies act as antagonists to competitively block cellular signaling pathways. We describe here an approach for the therapeutic use of monoclonal antibodies based on context-dependent attenuation to reduce pathologically high activity while allowing homeostatic signaling in biologically important pathways. Such attenuation is achieved by modulating the kinetics of a ligand binding to its various receptors and regulatory proteins rather than by complete blockade of signaling pathways. The anti-interleukin-1␤ (IL-1␤) antibody XOMA 052 is a potent inhibitor of IL-1␤ activity that reduces the affinity of IL-1␤ for its signaling receptor and co-receptor but not for its decoy and soluble inhibitory receptors. This mechanism shifts the effective dose response of the cytokine so that the potency of IL-1␤ bound by XOMA 052 is 20 -100-fold lower than that of IL-1␤ in the absence of antibody in a variety of in vitro cell-based assays. We propose that by decreasing potency of IL-1␤ while allowing binding to its clearance and inhibitory receptors, XOMA 052 treatment will attenuate IL-1␤ activity in concert with endogenous regulatory mechanisms. Furthermore, the ability to bind the decoy receptor may reduce the potential for accumulation of antibody⅐target complexes. Regulatory antibodies like XOMA 052, which selectively modulate signaling pathways, may represent a new mechanistic class of therapeutic antibodies.

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

Cited by 150 publications

References 61 publications

The role of caspase-8 in amyloid-induced beta cell death in human and mouse islets

The role of caspase-8 in amyloid-induced beta cell death in human and mouse islets

Pancreatic adenocarcinoma patients with localised chronic severe pancreatitis show an increased number of single beta cells, without alterations in fractional insulin area

Kinetic Approach to Pathway Attenuation Using XOMA 052, a Regulatory Therapeutic Antibody That Modulates Interleukin-1β Activity

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