Dual role of interleukin-1β in islet amyloid formation and its β-cell toxicity: Implications for type 2 diabetes and islet transplantation.

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.

Park YJ ，Warnock GL ，Ao Z ，Safikhan N ，Meloche M ，Asadi A ，Kieffer TJ ，Marzban L ... -  《-》

Amyloid formation disrupts the balance between interleukin-1β and interleukin-1 receptor antagonist in human islets.

Hui Q ，Asadi A ，Park YJ ，Kieffer TJ ，Ao Z ，Warnock GL ，Marzban L ... -  《Molecular Metabolism》

Amyloid formation reduces protein kinase B phosphorylation in primary islet β-cells which is improved by blocking IL-1β signaling.

Zhang Y ，Warnock GL ，Ao Z ，Park YJ ，Safikhan N ，Ghahary A ，Marzban L ... -  《PLoS One》

cJUN N-terminal kinase (JNK) activation mediates islet amyloid-induced beta cell apoptosis in cultured human islet amyloid polypeptide transgenic mouse islets.

Subramanian SL ，Hull RL ，Zraika S ，Aston-Mourney K ，Udayasankar J ，Kahn SE ... -  《-》

Deletion of Fas protects islet beta cells from cytotoxic effects of human islet amyloid polypeptide.

Park YJ ，Lee S ，Kieffer TJ ，Warnock GL ，Safikhan N ，Speck M ，Hao Z ，Woo M ，Marzban L ... -  《-》