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. 2010 Jun;87(6):1103-14.
doi: 10.1189/jlb.0509363. Epub 2010 Mar 3.

Differential Effects of Selective HDAC Inhibitors on Macrophage Inflammatory Responses to the Toll-like Receptor 4 Agonist LPS

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Differential Effects of Selective HDAC Inhibitors on Macrophage Inflammatory Responses to the Toll-like Receptor 4 Agonist LPS

Maria A Halili et al. J Leukoc Biol. .

Abstract

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.

Comment in

  • Cell death, it always matters.
    Comalada M, Serrat N, Xaus J. Comalada M, et al. J Leukoc Biol. 2010 Dec;88(6):1063-4; author reply 1065-6. doi: 10.1189/jlb.0710401. J Leukoc Biol. 2010. PMID: 21123293 No abstract available.

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