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

M. A. Halili, M. R. Andrews, L. I. Labzin, K. Schroder, G. Matthias, C. Cao, E. Lovelace, R. C. Reid, D. A. Hume, K. M. Irvine, P. Matthias, D. P. Fairlie, M. J. Sweet

Research output: Contribution to journalArticlepeer-review

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.
Original languageEnglish
Pages (from-to)1103-1114
Number of pages12
JournalJournal of Leukocyte Biology
Volume87
Issue number6
DOIs
Publication statusPublished - Jun 2010

Keywords

  • HDAC6
  • histone deacetylase
  • inflammation
  • sepsis
  • SAHA
  • TLR

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