HDAC Inhibitor-Mediated Beta-Cell Protection Against Cytokine-Induced Toxicity Is STAT1 Tyr701 Phosphorylation Independent
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HDAC Inhibitor-Mediated Beta-Cell Protection Against Cytokine-Induced Toxicity Is STAT1 Tyr701 Phosphorylation Independent. / Dahllöf, Mattias Salling; Christensen, Dan P; Harving, Mette; Wagner, Bridget K; Mandrup-Poulsen, Thomas; Lundh, Morten.
In: Journal of Interferon & Cytokine Research, Vol. 35, No. 1, 13.01.2015, p. 63-70.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - HDAC Inhibitor-Mediated Beta-Cell Protection Against Cytokine-Induced Toxicity Is STAT1 Tyr701 Phosphorylation Independent
AU - Dahllöf, Mattias Salling
AU - Christensen, Dan P
AU - Harving, Mette
AU - Wagner, Bridget K
AU - Mandrup-Poulsen, Thomas
AU - Lundh, Morten
PY - 2015/1/13
Y1 - 2015/1/13
N2 - Histone deacetylase (HDAC) inhibition protects pancreatic beta-cells against apoptosis induced by the combination of the proinflammatory cytokines interleukin (IL)-1β and interferon (IFN)-γ. Decreased expression of cell damage-related genes is observed on the transcriptional level upon HDAC inhibition using either IL-1β or IFN-γ alone. Whereas HDAC inhibition has been shown to regulate NFκB-activity, related primarily to IL-1β signaling, it is unknown whether the inhibition of HDACs affect IFN-γ signaling in beta-cells. Further, in non-beta-cells, there is a dispute whether HDAC inhibition regulates IFN-γ signaling at the level of STAT1 Tyr701 phosphorylation. Using different small molecule HDAC inhibitors with varying class selectivity, INS-1E wild type and stable HDAC1-3 knockdown pancreatic INS-1 cell lines, we show that IFN-γ-induced Cxcl9 and iNos expression as well as Cxcl9 and GAS reporter activity were decreased by HDAC inhibition in a STAT1 Tyr701 phosphorylation-independent fashion. In fact, knockdown of HDAC1 increased IFN-γ-induced STAT1 phosphorylation.
AB - Histone deacetylase (HDAC) inhibition protects pancreatic beta-cells against apoptosis induced by the combination of the proinflammatory cytokines interleukin (IL)-1β and interferon (IFN)-γ. Decreased expression of cell damage-related genes is observed on the transcriptional level upon HDAC inhibition using either IL-1β or IFN-γ alone. Whereas HDAC inhibition has been shown to regulate NFκB-activity, related primarily to IL-1β signaling, it is unknown whether the inhibition of HDACs affect IFN-γ signaling in beta-cells. Further, in non-beta-cells, there is a dispute whether HDAC inhibition regulates IFN-γ signaling at the level of STAT1 Tyr701 phosphorylation. Using different small molecule HDAC inhibitors with varying class selectivity, INS-1E wild type and stable HDAC1-3 knockdown pancreatic INS-1 cell lines, we show that IFN-γ-induced Cxcl9 and iNos expression as well as Cxcl9 and GAS reporter activity were decreased by HDAC inhibition in a STAT1 Tyr701 phosphorylation-independent fashion. In fact, knockdown of HDAC1 increased IFN-γ-induced STAT1 phosphorylation.
U2 - 10.1089/jir.2014.0022
DO - 10.1089/jir.2014.0022
M3 - Journal article
C2 - 25062500
VL - 35
SP - 63
EP - 70
JO - Journal of Interferon and Cytokine Research
JF - Journal of Interferon and Cytokine Research
SN - 1079-9907
IS - 1
ER -
ID: 119978068