Histone Deacetylase Inhibitor LAQ824 Augments Inflammatory Responses in Macrophages through Transcriptional Regulation of IL-10

Department of Immunology and Malignant Hematology, H. Lee Moffitt Cancer Center, Tampa, FL 33613, USA.
The Journal of Immunology (Impact Factor: 4.92). 03/2011; 186(7):3986-96. DOI: 10.4049/jimmunol.1001101
Source: PubMed


APCs are important in the initiation of productive Ag-specific T cell responses and the induction of T cell anergy. The inflammatory status of the APC at the time of encounter with Ag-specific T cells plays a central role in determining such divergent T cell outcomes. A better understanding of the regulation of proinflammatory and anti-inflammatory genes in its natural setting, the chromatin substrate, might provide novel insights to overcome anergic mechanisms mediated by APCs. In this study, we show for the first time, to our knowledge, that treatment of BALB/c murine macrophages with the histone deacetylase inhibitor LAQ824 induces chromatin changes at the level of the IL-10 gene promoter that lead to enhanced recruitment of the transcriptional repressors HDAC11 and PU.1. Such an effect is associated with diminished IL-10 production and induction of inflammatory cells able of priming naive Ag-specific T cells, but more importantly, capable of restoring the responsiveness of anergized Ag-specific CD4(+) T cells.

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Available from: Eduardo M Sotomayor, Feb 21, 2014
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    • "HDACi immunomodulatory properties are complex (Bode and Dalpke, 2011; Kroesen et al., 2014) and not simply anti-inflammatory (Leoni et al., 2002; Grabiec et al., 2008; Halili et al., 2009; Fairlie and Sweet, 2012). Treatment of mouse macrophages with Trichostatin (TSA) downregulates many inflammatory genes, thus compromising host defence (Roger et al., 2011), while they can also upregulate pro-inflammatory genes, and promote cytokine secretion (Wang et al., 2011; Kroesen et al., 2014). Indeed, we previously showed that TSA differentially regulates many inflammatory and pro-arthritic genes in human and mouse macrophages in response to toll-like receptor 4 (TLR4) "
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    • "Interestingly, HDACi also suppressed the expression of anti-inflammatory cytokines, such as IL-10 and TGFb (Figs. 5C, 6C). A similar effect was observed in mouse macrophages, in which treatment with the HDAC inhibitor LAQ824 resulted in reduced IL-10 expression (Wang et al., 2011). Subsequently, we carried out ELISA measurements to determine the effect of HDACi on the LPS-induced secretion of cytokines from microglia. "
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