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Inhibition of Tumor Necrosis Factor-α-induced Nuclear Translocation and Activation of NF-κB by Dehydroxymethylepoxyquinomicin

2002; Elsevier BV; Volume: 277; Issue: 27 Linguagem: Inglês

10.1074/jbc.m112063200

1083-351X

Akiko Ariga, Jun-ichi Namekawa, Naoki Matsumoto, Jun‐ichiro Inoue, Kazuo Umezawa,

Cytokine Signaling Pathways and Interactions

We previously designed and synthesized an NF-κB 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-α (TNF-α)- and 12- O -tetradecanoylphorbol-13-acetate-induced transcriptional activity of NF-κB in human T cell leukemia Jurkat cells. It also inhibited the TNF-α-induced DNA binding of nuclear NF-κB but not the phosphorylation and degradation of IκB. Moreover, DHMEQ inhibited the TNF-α-induced nuclear accumulation of p65, a component of NF-κB. It also inhibited TNF-α-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-α-induced activation of JNK but synergistically induced apoptosis with TNF-α in Jurkat cells. Taken together, these data indicate that DHMEQ is a unique inhibitor of NF-κB acting at the level of nuclear translocation.