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LPS regulates proinflammatory gene expression in macrophages by altering histone deacetylase expression

Hnin Thanda Aung^*,,,1, Kate Schroder^*,,,1, Stewart R. Himes^*,,, Kristian Brion^*,,, Wendy van Zuylen^*,,, Angela Trieu^*,,, Harukazu Suzuki, Yoshihide Hayashizaki, David A. Hume^*,,, Matthew J. Sweet^*,, and Timothy Ravasi^*,,,,2

^* Cooperative Research Centre for Chronic inflammatory Diseases and

Australian Research Council Special Research Centre for Functional and Applied Genomics, Institute for Molecular Bioscience, University of Queensland, Australia;

Laboratory for Genome Exploration Research Group, RIKEN Genomic Sciences Center, RIKEN Yokohama Institute, Tsurumi-ku, Yokohama, Japan; and

Department of Bioengineering, University of California, San Diego, California, USA

²Correspondence: Department of Bioengineering, University of California, San Diego, CA, USA. E-mail: travasi{at}bioeng.ucsd.edu

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, H. T., Schroder, K., Himes, S. R., Brion, K., van Zuylen, W., Trieu, A., Suzuki, H., Hayashizaki, Y., Hume, D. A., Sweet, M. J., Ravasi, T. LPS regulates proinflammatory gene expression in macrophages by altering histone deacetylase expression.

Key Words: transcriptional regulatory networks • epigenetic • histone code • innate immunity • inflammation

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