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)-1? and interferon (IFN)-?. Decreased expression of cell damage-related genes is observed on the transcriptional level upon HDAC inhibition using either IL-1? or IFN-? alone. Whereas HDAC inhibition has been shown to regulate NF?B-activity, related primarily to IL-1? signaling, it is unknown whether the inhibition of HDACs affect IFN-? signaling in beta-cells. Further, in non-beta-cells, there is a dispute whether HDAC inhibition regulates IFN-? 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-?-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-?-induced STAT1 phosphorylation.

SUBMITTER: Dahllof MS 

PROVIDER: S-EPMC4291159 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature