Inhibition of tumor necrosis factor-alpha -induced nuclear translocation and activation of NF-kappa B by dehydroxymethylepoxyquinomicin.
We previously designed and synthesized an NF-kappaB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), that showed anti-inflammatory activity in vivo. In the present study we looked into its mechanism of inhibition. DHMEQ inhibited tumor necrosis factor-alpha (TNF-alpha)- and 12-O-tetradecanoylphorbol-13-acetate-induced transcriptional activity of NF-kappaB in human T cell leukemia Jurkat cells. It also inhibited the TNF-alpha-induced DNA binding of nuclear NF-kappaB but not the phosphorylation and degradation of IkappaB. Moreover, DHMEQ inhibited the TNF-alpha-induced nuclear accumulation of p65, a component of NF-kappaB. It also inhibited TNF-alpha-induced nuclear transport of green fluorescent protein-tagged p65. On the other hand, DHMEQ did not inhibit the nuclear transport of Smad2 and large T antigen. Also, it did not inhibit TNF-alpha-induced activation of JNK but synergistically induced apoptosis with TNF-alpha in Jurkat cells. Taken together, these data indicate that DHMEQ is a unique inhibitor of NF-kappaB acting at the level of nuclear translocation.
Ariga
Akiko
A
Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama 223-0061, Japan.
Namekawa
Jun-Ichi
J
Matsumoto
Naoki
N
Inoue
Jun-Ichiro
J
Umezawa
Kazuo
K
D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000502:physiology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology*; D003512:Cyclohexanones / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D019169:Jurkat Cells; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D051899:Smad2 Protein; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D015534:Trans-Activators / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D001549:Benzamides; D003512:Cyclohexanones; D004268:DNA-Binding Proteins; D008164:Luminescent Proteins; D016328:NF-kappa B; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; C464444:dehydroxymethylepoxyquinomicin; D049452:Green Fluorescent Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D013755:Tetradecanoylphorbol Acetate