Differential effects of selective HDAC inhibitors on macrophage inflammatory responses to the Toll-like receptor 4 agonist LPS

Journal of Leukocyte Biology

Kate Schroder²  Maria A. Halili¹  Melanie R. Andrews¹  Katharine M. Irvine¹  Larisa I. Labzin¹  David A. Hume⁴  Chun Cao³  Erica Lovelace¹  Giang T. Le¹  Robert C. Reid¹  David P. Fairlie¹  Matthew J. Sweet¹  Patrick Matthias³  Gabriele Matthias³ 

[1] The University of Queensland, Institute for Molecular Bioscience, Brisbane, Queensland, Australia; The University of Queensland, Institute for Molecular Bioscience, Brisbane, Queensland, Australia; The University of Queensland, Institute for Molecular Bioscience, Brisbane, Queensland, Australia;Department of Biochemistry, University of Lausanne, Epalinges, Switzerland; Department of Biochemistry, University of Lausanne, Epalinges, Switzerland; Department of Biochemistry, University of Lausanne, Epalinges, Switzerland;;Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland; and Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland; and Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland; and;The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Scotland, United Kingdom The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Scotland, United Kingdom The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Scotland, United Kingdom

关键词: HDAC6;    histone deacetylase;    inflammation;    sepsis;    SAHA;    TLR;   

DOI  :  10.1189/jlb.0509363

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

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.

【 授权许可】

Unknown