E-73, an acetoxyl analogue of cycloheximide, blocks the tumor necrosis factor-induced NF-kappaB signaling pathway.
Proinflammatory cytokines such as tumor necrosis factor (TNF) and interleukin (IL)-1 activate the NF-kappaB signaling pathway which induces the expression of a variety of genes such as the encoding intercellular adhesion molecule (ICAM)-1. We have found that E-73, an acetoxyl analogue of cycloheximide, specifically blocks TNF-induced ICAM-1 expression even at concentrations unable to affect protein synthesis. By contrast, cycloheximide inhibited both TNF- and IL-1-induced ICAM-1 expression primarily due to the blockage of protein synthesis. The nuclear translocation of NF-kappaB as well as the IkappaB degradation induced by TNF, but not by IL-1, was significantly prevented by E-73. These observations suggest that E-73 blocks the TNF-induced NF-kappaB signaling pathway upstream of IkappaB degradation.
Sugimoto
H
H
Department of Bioengineering, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama, 226-8501, Japan.
Kataoka
T
T
Igarashi
M
M
Hamada
M
M
Takeuchi
T
T
Nagai
K
K
D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism; D003513:Cycloheximide / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D003600:Cytosol / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D010766:Phosphorylation; D011500:Protein Synthesis Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction; D051996:Transcription Factor RelA; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
C416002:E-73, acetoxyl cycloheximide analog; D020672:I-kappa B Proteins; D007375:Interleukin-1; D016328:NF-kappa B; D011500:Protein Synthesis Inhibitors; D011994:Recombinant Proteins; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D003513:Cycloheximide