Differential effects of selective HDAC inhibitors on macrophage inflammatory responses to the Toll-like receptor 4 agonist LPS.
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.
Halili
Maria A
MA
The University of Queensland, Institute for Molecular Bioscience, S. Lucia, Brisbane, Queensland, 4072, Australia.
Andrews
Melanie R
MR
Labzin
Larisa I
LI
Schroder
Kate
K
Matthias
Gabriele
G
Cao
Chun
C
Lovelace
Erica
E
Reid
Robert C
RC
Le
Giang T
GT
Hume
David A
DA
Irvine
Katharine M
KM
Matthias
Patrick
P
Fairlie
David P
DP
Sweet
Matthew J
MJ
D000818:Animals; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000737:chemistry* / Q000502:physiology; D006877:Hydroxamic Acids / Q000494:pharmacology; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D053762:Interleukin-12 Subunit p40 / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008156:Luciferases / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051197:Toll-Like Receptor 4 / Q000819:agonists* / Q000378:metabolism; D000077337:Vorinostat
D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D018836:Inflammation Mediators; D053762:Interleukin-12 Subunit p40; D008070:Lipopolysaccharides; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D051197:Toll-Like Receptor 4; C012589:trichostatin A; D000077337:Vorinostat; D008156:Luciferases; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases