The immunoproteasome is induced by cytokines and regulates apoptosis in human islets
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The immunoproteasome is induced by cytokines and regulates apoptosis in human islets. / Lundh, Morten; Bugliani, Marco; Dahlby, Tina; Chou, Danny Hung-Chieh; Wagner , Bridget; Ghiasi, Seyed Mojtaba; De Tata, Vincenzo; Chen, Zhifei; Lund, Marianne Nissen; Davies, Michael Jonathan; Marchetti, Piero; Mandrup-Poulsen, Thomas.
In: Journal of Endocrinology, Vol. 233, No. 3, 2017, p. 369-379.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - The immunoproteasome is induced by cytokines and regulates apoptosis in human islets
AU - Lundh, Morten
AU - Bugliani, Marco
AU - Dahlby, Tina
AU - Chou, Danny Hung-Chieh
AU - Wagner , Bridget
AU - Ghiasi, Seyed Mojtaba
AU - De Tata, Vincenzo
AU - Chen, Zhifei
AU - Lund, Marianne Nissen
AU - Davies, Michael Jonathan
AU - Marchetti, Piero
AU - Mandrup-Poulsen, Thomas
PY - 2017
Y1 - 2017
N2 - In addition to degrading misfolded and damaged proteins, the proteasome regulates the fate of cells in response to stress. The role of the proteasome in pro-inflammatory cytokine-induced human beta-cell apoptosis is unknown. Using INS-1, INS-1E and human islets exposed to combinations of IFNγ, IL-1β and TNFα with or without addition of small molecules, we assessed the role of the immunoproteasome in pancreatic beta-cell demise. Here, we show that cytokines induce the expression and activity of the immuno-proteasome in INS-1E cells and human islets. Cytokine-induced expression of immuno-proteasome subunits, but not activity, depended upon histone deacetylase 3 activation. Inhibition of JAK1/STAT1 signaling did not affect proteasomal activity. Inhibition of the immuno-proteasome subunit PSMB8 aggravated cytokine-induced human beta-cell apoptosis while reducing intracellular levels of oxidized proteins in INS-1 cells. While cytokines increased total cellular NFκB subunit P50 and P52 levels and reduced the cytosolic NFκB subunit P65 and IκB levels, these effects were unaffected by PSMB8 inhibition. We conclude that beta cells upregulate immuno-proteasome expression and activity in response to IFNγ, likely as a protective response to confine inflammatory signaling.
AB - In addition to degrading misfolded and damaged proteins, the proteasome regulates the fate of cells in response to stress. The role of the proteasome in pro-inflammatory cytokine-induced human beta-cell apoptosis is unknown. Using INS-1, INS-1E and human islets exposed to combinations of IFNγ, IL-1β and TNFα with or without addition of small molecules, we assessed the role of the immunoproteasome in pancreatic beta-cell demise. Here, we show that cytokines induce the expression and activity of the immuno-proteasome in INS-1E cells and human islets. Cytokine-induced expression of immuno-proteasome subunits, but not activity, depended upon histone deacetylase 3 activation. Inhibition of JAK1/STAT1 signaling did not affect proteasomal activity. Inhibition of the immuno-proteasome subunit PSMB8 aggravated cytokine-induced human beta-cell apoptosis while reducing intracellular levels of oxidized proteins in INS-1 cells. While cytokines increased total cellular NFκB subunit P50 and P52 levels and reduced the cytosolic NFκB subunit P65 and IκB levels, these effects were unaffected by PSMB8 inhibition. We conclude that beta cells upregulate immuno-proteasome expression and activity in response to IFNγ, likely as a protective response to confine inflammatory signaling.
U2 - 10.1530/JOE-17-0110
DO - 10.1530/JOE-17-0110
M3 - Journal article
C2 - 28438776
VL - 233
SP - 369
EP - 379
JO - Journal of Endocrinology
JF - Journal of Endocrinology
SN - 0022-0795
IS - 3
ER -
ID: 178799094