LPS regulates proinflammatory gene expression in macrophages by altering histone deacetylase expression.
Bacterial LPS triggers dramatic changes in gene expression in macrophages. We show here that LPS regulated several members of the histone deacetylase (HDAC) family at the mRNA level in murine bone marrow-derived macrophages (BMM). LPS transiently repressed, then induced a number of HDACs (Hdac-4, 5, 7) in BMM, whereas Hdac-1 mRNA was induced more rapidly. Treatment of BMM with trichostatin A (TSA), an inhibitor of HDACs, enhanced LPS-induced expression of the Cox-2, Cxcl2, and Ifit2 genes. In the case of Cox-2, this effect was also apparent at the promoter level. Overexpression of Hdac-8 in RAW264 murine macrophages blocked the ability of LPS to induce Cox-2 mRNA. Another class of LPS-inducible genes, which included Ccl2, Ccl7, and Edn1, was suppressed by TSA, an effect most likely mediated by PU.1 degradation. Hence, HDACs act as potent and selective negative regulators of proinflammatory gene expression and act to prevent excessive inflammatory responses in macrophages.
Aung
Hnin Thanda
HT
Cooperative Research Centre for Chronic inflammatory Diseases, Institute for Molecular Bioscience, University of Queensland, Australia.
Schroder
Kate
K
Himes
Stewart R
SR
Brion
Kristian
K
van Zuylen
Wendy
W
Trieu
Angela
A
Suzuki
Harukazu
H
Hayashizaki
Yoshihide
Y
Hume
David A
DA
Sweet
Matthew J
MJ
Ravasi
Timothy
T
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002460:Cell Line; D003001:Cloning, Molecular; D051546:Cyclooxygenase 2 / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000235:genetics*; D006877:Hydroxamic Acids / Q000494:pharmacology; D007249:Inflammation / Q000235:genetics*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D008070:Lipopolysaccharides; C012589:trichostatin A; D051546:Cyclooxygenase 2; D006655:Histone Deacetylases