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Tumor Necrosis Factor Alpha-Mediated Reduction of KLF2 Is Due to Inhibition of MEF2 by NF-B and Histone Deacetylases

Program in Cardiovascular Transcriptional Biology, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, Massachusetts 02115

Received 9 December 2004/ Returned for modification 18 January 2005/ Accepted 7 April 2005

Activation of the endothelium by inflammatory cytokines is a key event in the pathogenesis of vascular disease states. Proinflammatory cytokines repress the expression of KLF2, a recently identified transcriptional inhibitor of the cytokine-mediated activation of endothelial cells. In this study the molecular basis for the cytokine-mediated inhibition of KLF2 is elucidated. Tumor necrosis factor alpha (TNF-) potently inhibited KLF2 expression. This effect was completely abrogated by a constitutively active form of IB, as well as treatment with trichostatin A, implicating a role for the NF-B pathway and histone deacetylases. Overexpression studies coupled with observations with p50/p65 null cells support an essential role for p65. A combination of promoter deletion and mutational analyses, chromatin immunoprecipitation assays, and coimmunoprecipitation studies indicates that p65 and histone deacetylases 4 cooperate to inhibit the ability of MEF2 factors to induce the KLF2 promoter. These studies identify a novel mechanism by which TNF- can inhibit endothelial gene expression. Furthermore, the inhibition of MEF2 function by p65 and HDAC4 has implications for other cellular systems where these factors are operative.

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