Open AccessTumor Necrosis Factor Alpha-Mediated Reduction of KLF2 Is Due to Inhibition of MEF2 by NF-κB and Histone Deacetylases
Author(s) -
Ajay Kumar,
Zhiyong Lin,
Sucharita SenBanerjee,
Mukesh K. Jain
Publication year - 2005
Publication title -
molecular and cellular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.14
H-Index - 327
eISSN - 1067-8824
pISSN - 0270-7306
DOI - 10.1128/mcb.25.14.5893-5903.2005
Subject(s) - klf2 , biology , chromatin immunoprecipitation , trichostatin a , proinflammatory cytokine , histone , tumor necrosis factor alpha , mef2 , hdac4 , cancer research , nf κb , transcription factor , transactivation , histone deacetylase inhibitor , microbiology and biotechnology , nfkb1 , cytokine , histone deacetylase , signal transduction , gene expression , immunology , promoter , inflammation , biochemistry , enhancer , gene
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-alpha) potently inhibited KLF2 expression. This effect was completely abrogated by a constitutively active form of IkappaBalpha, as well as treatment with trichostatin A, implicating a role for the NF-kappaB 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 co-immunoprecipitation 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-alpha 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.