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

被引:360
作者
Ninomiya-Tsuji, J
Kajino, T
Ono, K
Ohtomo, T
Matsumoto, M
Shiina, M
Mihara, M
Tsuchiya, M
Matsumoto, K [1 ]
机构
[1] Nagoya Univ, Grad Sch Sci, Dept Mol Biol, Chikusa Ku, Nagoya, Aichi 4648602, Japan
[2] Japan Sci & Technol Corp, CREST, Chikusa Ku, Nagoya, Aichi 4648602, Japan
[3] Chugai Pharmaceut Co Ltd, Fuji Gotemba Res Labs, Gotemba, Shizuoka 4128513, Japan
[4] N Carolina State Univ, Dept Environm & Mol Toxicol, Raleigh, NC 27695 USA
关键词
D O I
10.1074/jbc.M207453200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:18485 / 18490
页数:6
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