A resorcylic acid lactone, 5Z-7-oxozeaenol, prevents inflammation by inhibiting the catalytic activity of TAK1 MAPK kinase kinase.

TAK1, a member of the mitogen-activated kinase kinase kinase (MAPKKK) family, participates in proinflammatory cellular signaling pathways by activating JNK/p38 MAPKs and NF-kappaB. To identify drugs that prevent inflammation, we screened inhibitors of TAK1 catalytic activity. We identified a natural resorcylic lactone of fungal origin, 5Z-7-oxozeaenol, as a highly potent ...
inhibitor of TAK1. This compound did not effectively inhibit the catalytic activities of the MEKK1 or ASK1 MAPKKKs, suggesting that 5Z-7-oxozeaenol is a selective inhibitor of TAK1. In cell culture, 5Z-7-oxozeaenol blocked interleukin-1-induced activation of TAK1, JNK/p38 MAPK, IkappaB kinases, and NF-kappaB, resulting in inhibition of cyclooxgenase-2 production. Furthermore, in vivo 5Z-7-oxozeaenol was able to inhibit picryl chloride-induced ear swelling. Thus, 5Z-7-oxozeaenol blocks proinflammatory signaling by selectively inhibiting TAK1 MAPKKK.
Mesh Terms:
Animals, Anti-Inflammatory Agents, Cell Line, Cells, Cultured, Cyclooxygenase 2, Dose-Response Relationship, Drug, Enzyme Activation, Female, Genes, Reporter, Genetic Vectors, Humans, Immunoblotting, Inflammation, Inhibitory Concentration 50, Interleukin-1, Isoenzymes, Lactones, MAP Kinase Kinase Kinases, MAP Kinase Signaling System, Membrane Proteins, Mice, Mice, Inbred BALB C, Mitogen-Activated Protein Kinases, Models, Chemical, Precipitin Tests, Prostaglandin-Endoperoxide Synthases, Protein Binding, Signal Transduction, Time Factors, Transfection, Zearalenone, p38 Mitogen-Activated Protein Kinases
J. Biol. Chem.
Date: May. 16, 2003
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