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.
Kumar
Ajay
A
Program in Cardiovascular Transcriptional Biology, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, 75 Francis St. TH1127, Boston, Massachusetts 02115, USA.
Lin
Zhiyong
Z
SenBanerjee
Sucharita
S
Jain
Mukesh K
MK
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