15-deoxy-Δ12,14-prostaglandin J2 inhibits multiple steps in the NF-κB signaling pathway
15-deoxy-Δ12,14-prostaglandin J2 inhibits multiple steps in the NF-κB signaling pathway
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DOI：
10.1073/pnas.97.9.4844
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发表时间：
2000-04-25
影响因子：
11.1
通讯作者：
Glass, CK
中科院分区：
文献类型：
--
作者：
Straus, DS;Pascual, G;Glass, CK
前列腺素 J(2)(PGJ(2)) 及其代谢物 Delta(12)-PGJ(2) 和 15-脱氧-Delta(12,14)-PGJ(2) (15d-PGJ(2)) 是前列腺素 D-2 的天然衍生物，已被认为在体内发挥抗炎作用。 15d-PGJ(2) 是过氧化物酶体增殖物激活受体 γ (pPAP γ) 的高亲和力配体，已被证明能够以 PPAR γ 依赖性方式抑制炎症反应基因的诱导，包括诱导型 NO 合酶和肿瘤坏死因子 α。我们在此报告，15d-PGJ(2) 通过另外两种 PPAR gamma 独立机制有效抑制 NF-kappa B 依赖性转录。多项证据表明，15d-PGJ(2) 通过共价修饰 I kappa B 激酶中的关键半胱氨酸残基和 NF-kappa B 亚基的 DNA 结合域，直接抑制 NF-kappa B 依赖性基因表达。这些机制联合作用，抑制 NF-kappa B 靶基因环氧合酶 2 的反式激活，15d-PGJ(2) 直接抑制 NF-kappa B 信号传导可能有助于前列腺素生物合成和炎症的负调节，这表明开发抗炎药物的其他方法。
Prostaglandin J(2)(PGJ(2)) and its metabolites Delta(12)-PGJ(2) and 15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)) are naturally occurring derivatives of prostaglandin D-2 that have been suggested to exert antiinflammatory effects in vivo. 15d-PGJ(2) is a high-affinity ligand for the peroxisome proliferator-activated receptor gamma (pPAP gamma) and has been demonstrated to inhibit the induction of inflammatory response genes, including inducible NO synthase and tumor necrosis factor alpha, in a PPAR gamma-dependent manner. We report here that 15d-PGJ(2) potently inhibits NF-kappa B-dependent transcription by two additional PPAR gamma-independent mechanisms. Several lines of evidence suggest that 15d-PGJ(2) directly inhibits NF-kappa B-dependent gene expression through covalent modifications of critical cysteine residues in I kappa B kinase and the DNA-binding domains of NF-kappa B subunits. These mechanisms act in combination to inhibit transactivation of the NF-kappa B target gene cyclooxygenase 2, Direct inhibition of NF-kappa B signaling by 15d-PGJ(2) may contribute to negative regulation of prostaglandin biosynthesis and inflammation, suggesting additional approaches to the development of antiinflammatory drugs.