A resorcylic acid lactone, 5Z-7-oxozeaenol, prevents inflammation by inhibiting the catalytic activity of TAK1 MAPK kinase kinase
A resorcylic acid lactone, 5Z-7-oxozeaenol, prevents inflammation by inhibiting the catalytic activity of TAK1 MAPK kinase kinase
复制标题
DOI：
10.1074/jbc.m207453200
复制
发表时间：
2003-05-16
影响因子：
4.8
通讯作者：
Matsumoto, K
中科院分区：
文献类型：
--
作者：
Ninomiya-Tsuji, J;Kajino, T;Matsumoto, K
TAK1是丝裂原激活激酶(MAPKKK)家族的成员，通过激活JNK/p38MAPKs和NF-kappaB参与促炎细胞信号转导通路。为了确定预防炎症的药物，我们筛选了TAK1催化活性的抑制剂。我们鉴定了一种来自真菌的天然间苯二环内酯，5Z-7-氧代玉米赤霉烯醇，是一种高效的TAK1抑制剂。该化合物不能有效地抑制MEKK1或ASK1 MAPKKKs的催化活性，提示5Z-7-oxozeaenol是TAK1的选择性抑制剂。在细胞培养中，5Z-7-oxozeaenol阻断了IL-1诱导的TAK1、JNK/p38MAPK、IkappaB激酶和NF-kappaB的激活，从而抑制了环氧合酶-2的产生。此外，在体内，5Z-7-oxozeaenol可抑制苦味酸引起的小鼠耳肿胀。因此，5Z-7-oxozeaenol通过选择性抑制TAK1 MAPKKK来阻断促炎信号。
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.