title: Dual role of interleukin-1β in islet amyloid formation and its β-cell toxicity: Implications for type 2 diabetes and islet transplantation.
abstract: Islet amyloid, formed by aggregation of human islet amyloid polypeptide (hIAPP), contributes to β-cell failure in type 2 diabetes, cultured and transplanted islets. We previously showed that biosynthetic hIAPP aggregates induce β-cell Fas upregulation and activation of the Fas apoptotic pathway. We used cultured human and hIAPP-expressing mouse islets to investigate: (1) the role of interleukin-1β (IL-1β) in amyloid-induced Fas upregulation; and (2) the effects of IL-1β-induced β-cell dysfunction on pro-islet amyloid polypeptide (proIAPP) processing and amyloid formation.
  
  
  
  Human and h IAPP -expressing mouse islets were cultured to form amyloid without or with the IL-1 receptor antagonist (IL-1Ra) anakinra, in the presence or absence of recombinant IL-1β. Human islets in which amyloid formation was prevented (amyloid inhibitor or Ad-prohIAPP-siRNA) were cultured similarly. β-cell function, apoptosis, Fas expression, caspase-8 activation, islet IL-1β, β-cell area, β-/α-cell ratio, amyloid formation, and (pro)IAPP forms were assessed.
  
  
  
  hIAPP aggregates were found to increase IL-1β levels in cultured human islets that correlated with β-cell Fas upregulation, caspase-8 activation and apoptosis, all of which were reduced by IL-1Ra treatment or prevention of amyloid formation. Moreover, IL-1Ra improved culture-induced β-cell dysfunction and restored impaired proIAPP processing, leading to lower amyloid formation. IL-1β treatment potentiated impaired proIAPP processing and increased amyloid formation in cultured human and h IAPP -expressing mouse islets, which were prevented by IL-1Ra.
  
  
  
  IL-1β plays a dual role by: (1) mediating amyloid-induced Fas upregulation and β-cell apoptosis; (2) inducing impaired proIAPP processing thereby potentiating amyloid formation. Blocking IL-1β may provide a new strategy to preserve β cells in conditions associated with islet amyloid formation.
authors.affiliation: Department of Surgery, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Yoo Jin
authors.initials: YJ
authors.lastname: Park
authors.affiliation: Department of Surgery, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Garth L
authors.initials: GL
authors.lastname: Warnock
authors.affiliation: Department of Surgery, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Ziliang
authors.initials: Z
authors.lastname: Ao
authors.affiliation: Department of Surgery, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Nooshin
authors.initials: N
authors.lastname: Safikhan
authors.affiliation: Department of Surgery, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Meloche
authors.affiliation: Department of Cellular and Physiological Sciences, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Ali
authors.initials: A
authors.lastname: Asadi
authors.affiliation: Department of Surgery, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.|Department of Cellular and Physiological Sciences, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Kieffer
authors.affiliation: Department of Surgery, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Lucy
authors.identifier: 0000-0003-1903-5257
authors.initials: L
authors.lastname: Marzban
mesh_terms: D000328:Adult; D000682:Amyloid / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D002102:Cadaver; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D057898:Hemizygote; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D058228:Islet Amyloid Polypeptide / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D016381:Islets of Langerhans Transplantation / Q000009:adverse effects; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D011498:Protein Precursors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D034622:RNA Interference; D011994:Recombinant Proteins / Q000378:metabolism; D046509:Tissue Culture Techniques; D019014:fas Receptor / Q000819:agonists* / Q000378:metabolism
chemical_list: D000682:Amyloid; C491901:FAS protein, human; C508585:IL1B protein, human; C507763:IL1RN protein, human; D007328:Insulin; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D058228:Islet Amyloid Polypeptide; D011498:Protein Precursors; D011994:Recombinant Proteins; D019014:fas Receptor
keywords: amylin; interleukin-1β; islet amyloid; islet amyloid polypeptide; islet inflammation; islet transplantation; type 2 diabetes; β-cell apoptosis