Anti-inflammatory cyclopentenone prostaglandins are direct inhibitors of IκB kinase
Anti-inflammatory cyclopentenone prostaglandins are direct inhibitors of IκB kinase
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DOI：
10.1038/47520
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发表时间：
2000-01-06
期刊：
影响因子：
64.8
通讯作者：
Santoro, MG
中科院分区：
文献类型：
--
作者：
Rossi, A;Kapahi, P;Santoro, MG
NF-κ B是参与炎症和免疫的基因的关键激活剂（1，2）。促炎细胞因子激活I κ B激酶（IKK）复合物，使NF-κ B抑制剂磷酸化，触发它们与泛素结合并随后降解（3，4）。释放的NF-κ B二聚体易位至细胞核并诱导靶基因，包括催化促炎性前列腺素合成的环加氧酶2（COX 2）基因，特别是pGE（5，6）。然而，在炎症发作的晚期阶段，COX 2指导抗炎环戊烯酮类化合物的合成，表明这些分子在炎症消退中的作用（7）。已经表明环戊烯酮野牡丹素通过激活过氧化物酶体增殖物激活受体-γ发挥抗炎活性（参考文献8、9）。在这里，我们证明了一种新的IKK活性机制，该机制基于IKK的IKK β亚基的直接抑制和修饰。由于IKK β负责通过促炎刺激激活NF-κ B（10，11），我们的发现解释了环戊烯酮异黄酮的功能，并可用于改善COX 2抑制剂的效用。
NF-kappa B is a critical activator of genes involved in inflammation and immunity(1,2). Pro-inflammatory cytokines activate the I kappa B kinase (IKK) complex that phosphorylates the NF-kappa B inhibitors, triggering their conjugation with ubiquitin and subsequent degradation(3,4). Freed NF-kappa B dimers translocate to the nucleus and induce target genes, including the one for cyclo-oxygenase 2 (COX2), which catalyses the synthesis of pro-inflammatory prostaglandins, in particular pGE(5,6). At late stages of inflammatory episodes, however, COX2 directs the synthesis of anti-inflammatory cyclopentenone prostaglandins, suggesting a role for these molecules in the resolution of inflammation(7). Cyclopentenone prostaglandins have been suggested to exert anti-inflammatory activity through the activation of peroxisome proliferator-activated receptor-gamma (refs 8, 9). Here we demonstrate a novel mechanism of antiinflammatory activity which is based on the direct inhibition and modification of the IKK beta subunit of IKK, As IKK beta is responsible for the activation of NF-kappa B by pro-inflammatory stimuli(10,11), our findings explain how cyclopentenone prostaglandins function and can be used to improve the utility of COX2 inhibitors.