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Differential effects of selective HDAC inhibitors on macrophage inflammatory responses to the Toll-like receptor 4 agonist LPS.
Journal of Leukocyte Biology
Date de publication
Broad-spectrum inhibitors of HDACs are therapeutic in many inflammatory disease models but exacerbated disease in a mouse model of atherosclerosis. HDAC inhibitors have anti- and proinflammatory effects on macrophages in vitro. We report here that several broad-spectrum HDAC inhibitors, including TSA and SAHA, suppressed the LPS-induced mRNA expression of the proinflammatory mediators Edn-1, Ccl-7/MCP-3, and Il-12p40 but amplified the expression of the proatherogenic factors Cox-2 and Pai-1/serpine1 in primary mouse BMM. Similar effects were also apparent in LPS-stimulated TEPM and HMDM. The pro- and anti-inflammatory effects of TSA were separable over a concentration range, implying that individual HDACs have differential effects on macrophage inflammatory responses. The HDAC1-selective inhibitor, MS-275, retained proinflammatory effects (amplification of LPS-induced expression of Cox-2 and Pai-1 in BMM) but suppressed only some inflammatory responses. In contrast, 17a (a reportedly HDAC6-selective inhibitor) retained anti-inflammatory but not proinflammatory properties. Despite this, HDAC6(-/-) macrophages showed normal LPS-induced expression of HDAC-dependent inflammatory genes, arguing that the anti-inflammatory effects of 17a are not a result of inhibition of HDAC6 alone. Thus, 17a provides a tool to identify individual HDACs with proinflammatory properties.
Animals, Blotting, Western, Chromatin Immunoprecipitation, Cyclooxygenase 2/genetics, Cyclooxygenase 2/metabolism, Enzyme-Linked Immunosorbent Assay, Histone Deacetylase Inhibitors/pharmacology, Histone Deacetylases/chemistry, Histone Deacetylases/physiology, Hydroxamic Acids/pharmacology, Inflammation/immunology, Inflammation/metabolism, Inflammation Mediators/metabolism, Interleukin-12 Subunit p40/genetics, Interleukin-12 Subunit p40/metabolism, Lipopolysaccharides/pharmacology, Luciferases/metabolism, Macrophages/cytology, Macrophages/drug effects, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Plasminogen Activator Inhibitor 1/genetics, Plasminogen Activator Inhibitor 1/metabolism, RNA, Messenger/genetics, RNA, Messenger/metabolism, Reverse Transcriptase Polymerase Chain Reaction, Toll-Like Receptor 4/agonists, Toll-Like Receptor 4/metabolism
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