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.
Ninomiya-Tsuji
Jun
J
Department of Molecular Biology, Graduate School of Science, Nagoya University, and CREST, Japan Science and Technology Corporation, Chikusa-ku, Nagoya 464-8602, Japan.
Kajino
Taisuke
T
Ono
Koichiro
K
Ohtomo
Toshihiko
T
Matsumoto
Masahiko
M
Shiina
Masashi
M
Mihara
Masahiko
M
Tsuchiya
Masayuki
M
Matsumoto
Kunihiro
K
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005260:Female; D017930:Genes, Reporter; D005822:Genetic Vectors; D006801:Humans; D015151:Immunoblotting; D007249:Inflammation; D020128:Inhibitory Concentration 50; D007375:Interleukin-1 / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D007783:Lactones / Q000737:chemistry*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008956:Models, Chemical; D011233:Precipitin Tests; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011485:Protein Binding; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D015025:Zearalenone / Q000031:analogs & derivatives / Q000737:chemistry* / Q000494:pharmacology* / Q000008:administration & dosage; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7; D012118:Resorcinols
D000893:Anti-Inflammatory Agents; D051546:Cyclooxygenase 2; D007375:Interleukin-1; D007527:Isoenzymes; D007783:Lactones; D020930:MAP Kinase Kinase Kinases; D008565:Membrane Proteins; D020928:Mitogen-Activated Protein Kinases; D011451:Prostaglandin-Endoperoxide Synthases; D015025:Zearalenone; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7; C505734:7-oxozeanol; D012118:Resorcinols; C496540:PTGS2 protein, human