The immunoproteasome is induced by cytokines and regulates apoptosis in human islets

Morten Lundh; Marco Bugliani; Tina Dahlby; Danny Hung-Chieh Chou; Bridget Wagner; Seyed Mojtaba Ghiasi; Vincenzo De Tata; Zhifei Chen; Marianne Nissen Lund; Michael Jonathan Davies; Piero Marchetti; Thomas Mandrup-Poulsen

doi:10.1530/joe-17-0110

The immunoproteasome is induced by cytokines and regulates apoptosis in human islets

Morten Lundh, Marco Bugliani, Tina Dahlby, Danny Hung-Chieh Chou, Bridget Wagner , Seyed Mojtaba Ghiasi, Vincenzo De Tata, Zhifei Chen, Marianne Nissen Lund, Michael Jonathan Davies, Piero Marchetti, Thomas Mandrup-Poulsen

14 Citationer (Scopus)

Abstract

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.

Originalsprog	Engelsk
Tidsskrift	Journal of Endocrinology
Vol/bind	233
Udgave nummer	3
Sider (fra-til)	369-379
Antal sider	11
ISSN	0022-0795
DOI	https://doi.org/10.1530/joe-17-0110
Status	Udgivet - 1 jun. 2017

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title = "The immunoproteasome is induced by cytokines and regulates apoptosis in human islets",

abstract = "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. ",

author = "Morten Lundh and Marco Bugliani and Tina Dahlby and Chou, {Danny Hung-Chieh} and Bridget Wagner and Ghiasi, {Seyed Mojtaba} and {De Tata}, Vincenzo and Zhifei Chen and Lund, {Marianne Nissen} and Davies, {Michael Jonathan} and Piero Marchetti and Thomas Mandrup-Poulsen",

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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 - 2017/6/1

Y1 - 2017/6/1

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

SN - 0022-0795

VL - 233

SP - 369

EP - 379

JO - Journal of Endocrinology

JF - Journal of Endocrinology

IS - 3

ER -

The immunoproteasome is induced by cytokines and regulates apoptosis in human islets

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