Tumor necrosis factor alpha-mediated reduction of KLF2 is due to inhibition of MEF2 by NF-kappaB and histone deacetylases.
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.
Program in Cardiovascular Transcriptional Biology, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, 75 Francis St. TH1127, Boston, Massachusetts 02115, USA.
Ajay
A
Kumar
Zhiyong
Z
Lin
Sucharita
S
SenBanerjee
Mukesh K
MK
Jain
D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D051741:Kruppel-Like Transcription Factors; D064326:MEF2 Transcription Factors; D009154:Mutation; D018006:Myogenic Regulatory Factors; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000502:physiology; D012097:Repressor Proteins / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D051996:Transcription Factor RelA; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology / Q000502:physiology*
D004268:DNA-Binding Proteins; C096161:KLF2 protein, human; D051741:Kruppel-Like Transcription Factors; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; D016328:NF-kappa B; D012097:Repressor Proteins; D015534:Trans-Activators; D051996:Transcription Factor RelA; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; C400300:HDAC4 protein, human; D006655:Histone Deacetylases