HDAC Inhibitor-Mediated Beta-Cell Protection Against Cytokine-Induced Toxicity Is STAT1 Tyr701 Phosphorylation Independent

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