Regulation of the β-cell inflammasome and contribution to stress-induced cellular dysfunction and apoptosis

Seyed Mojtaba Ghiasi, Mattias Salling Dahllöf, Yama Osmai, Mirwais Osmai, Kathrine Kronberg Jakobsen, Alexander Aivazidis, Björn Tyrberg, Lisa Perruzza, Michala Cecilie Burstein Prause, Dan Ploug Christensen, Morten Fog-Tonnesen, Morten Lundh, Fabio Grassi, Lucienne Chatenoud, Thomas Mandrup-Poulsen


β-Cells may be a source of IL-1β that is produced as inactive pro-IL-1β and processed into biologically-active IL-1β by enzymatic cleavage mediated by the NLRP1-, NLRP3- and NLRC4-inflammasomes. Little is known about the β-cell inflammasomes. NLRP1-expression was upregulated in islet-cells from T2D-patients and by IL-1β+IFNγ in INS-1 cells in a histone-deacetylase dependent manner. NLRP3 was downregulated by cytokines in INS-1 cells. NLRC4 was barely expressed and not regulated by cytokines. High extracellular K+ reduced cytokine-induced apoptosis and NO production and restored cytokine-inhibited accumulated insulin-secretion. Basal inflammasome expression was JNK1-3 dependent. Knock-down of the ASC interaction domain common for NLRP1 and 3 improved insulin secretion and ameliorated IL-1β and/or glucolipotoxicity-induced cell death and reduced cytokine-induced NO-production. Broad inflammasome-inhibition, but not NLRP3-selective inhibition, protected against IL-1β-induced INS-1 cell-toxicity. We suggest that IL-1β causes β-cell toxicity in part by NLRP1 mediated caspase-1-activation and maturation of IL-1β leading to an autocrine potentiation loop.

TidsskriftMolecular and Cellular Endocrinology
Sider (fra-til)106-114
Antal sider9
StatusUdgivet - 15 dec. 2018


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