Regulation of the beta-cell inflammasome and contribution to stress-induced cellular dysfunction and apoptosis
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Regulation of the beta-cell inflammasome and contribution to stress-induced cellular dysfunction and apoptosis. / Ghiasi, Seyed Mojtaba; Dahllöf, Mattias Salling; Osmai, Yama; Osmai, Mirwais; Jakobsen, Kathrine Kronberg; Aivazidis, Alexander; Tyrberg, Björn; Perruzza, Lisa; Prause, Michala Cecilie Burstein; Christensen, Dan Ploug; Fog-Tonnesen, Morten; Lundh, Morten; Grassi, Fabio; Chatenoud, Lucienne; Mandrup-Poulsen, Thomas.
In: Molecular and Cellular Endocrinology, Vol. 478, 2018, p. 106-114.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Regulation of the beta-cell inflammasome and contribution to stress-induced cellular dysfunction and apoptosis
AU - Ghiasi, Seyed Mojtaba
AU - Dahllöf, Mattias Salling
AU - Osmai, Yama
AU - Osmai, Mirwais
AU - Jakobsen, Kathrine Kronberg
AU - Aivazidis, Alexander
AU - Tyrberg, Björn
AU - Perruzza, Lisa
AU - Prause, Michala Cecilie Burstein
AU - Christensen, Dan Ploug
AU - Fog-Tonnesen, Morten
AU - Lundh, Morten
AU - Grassi, Fabio
AU - Chatenoud, Lucienne
AU - Mandrup-Poulsen, Thomas
N1 - Copyright © 2018. Published by Elsevier B.V.
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85052079320&partnerID=8YFLogxK
U2 - 10.1016/j.mce.2018.08.001
DO - 10.1016/j.mce.2018.08.001
M3 - Journal article
C2 - 30121202
VL - 478
SP - 106
EP - 114
JO - Molecular and Cellular Endocrinology
JF - Molecular and Cellular Endocrinology
SN - 0303-7207
ER -
ID: 201419580