title: HDAC inhibitor-mediated beta-cell protection against cytokine-induced toxicity is STAT1 Tyr701 phosphorylation independent.
abstract: 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.
authors: 1 Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen, Denmark .
authors: Mattias S
authors: MS
authors: Dahllöf
authors: Dan P
authors: DP
authors: Christensen
authors: Mette
authors: M
authors: Harving
authors: Bridget K
authors: BK
authors: Wagner
authors: Thomas
authors: T
authors: Mandrup-Poulsen
authors: Morten
authors: M
authors: Lundh
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002219:Carbamates / Q000494:pharmacology; D002460:Cell Line; D054357:Chemokine CXCL10 / Q000096:biosynthesis; D054370:Chemokine CXCL9 / Q000096:biosynthesis; D056284:Histone Deacetylase 1 / Q000235:genetics*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics*; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000276:immunology*; D007371:Interferon-gamma / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis*; D010766:Phosphorylation; D051381:Rats; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D000099186:Histone Deacetylase 3
chemical_list: D002219:Carbamates; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D056284:Histone Deacetylase 1; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D007371:Interferon-gamma; D053583:Interleukin-1beta; D016328:NF-kappa B; D052247:Nitric Oxide Synthase Type II; D050794:STAT1 Transcription Factor; D000099186:Histone Deacetylase 3; C505723:CXCL9 protein, rat; C091326:Cxcl10 protein, rat; C000594089:IL1B protein, rat; C494081:Stat1 protein, rat; C575255:givinostat; C496318:Nos2 protein, rat; C515890:Hdac1 protein, rat