Melatonin suppresses macrophage cyclooxygenase-2 and inducible nitric oxide synthase expression by inhibiting p52 acetylation and binding
Melatonin suppresses macrophage cyclooxygenase-2 and inducible nitric oxide synthase expression by inhibiting p52 acetylation and binding
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DOI：
10.1182/blood-2005-09-3691
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发表时间：
2006-07-15
期刊：
影响因子：
20.3
通讯作者：
Wu, Kenneth K.
中科院分区：
文献类型：
--
作者：
Deng, Wu-Guo;Tang, Shao-Tzu;Wu, Kenneth K.
褪黑激素已被证明由非松果体细胞产生，并在动物模型中具有抗炎作用。在本研究中，我们测试了这样的假设：褪黑激素通过常见的转录机制抑制环氧合酶-2 (COX2) 和诱导型一氧化氮合酶 (INOS) 等促炎基因的表达。褪黑激素而非色氨酸或血清素以时间和浓度依赖性方式抑制 RAW 264.7 细胞中脂多糖 (LPS) 诱导的 COX-2 和 iNOS 蛋白水平和启动子活性。 LPS 或 LPS 加干扰素-γ (IFN gamma) 增加了 NF-κ B 的所有 5 种亚型与 COX-2 和 iNOS 启动子的结合。褪黑激素选择性抑制 p52 结合，而不影响 p100 表达、p100 生成 p52 或 p52 核转位。 LPS 增强 p52 乙酰化，而褪黑激素则消除这种乙酰化。褪黑激素抑制 p300 组蛋白乙酰转移酶 (HAT) 活性并消除 p300 增强的 COX-2 和 iNOS 表达。 HAT 抑制剂抑制 LPS 诱导的 p52 结合和乙酰化的程度与褪黑激素相似，并且褪黑激素不会增强 HAT 抑制剂的作用。这些结果表明，褪黑素通过抑制 p300 HAT 活性来抑制 COX-2 和 iNOS 转录激活，从而抑制 p52 乙酰化、结合和反式激活。
Melatonin has been shown to be produced by nonpineal cells and possess anti-inflammatory actions in animal models. In the present study, we tested the hypothesis that melatonin suppresses the expression of proinflammatory genes such as cyclooxygenase-2 (COX2) and inducible nitric oxide synthase (INOS) by a common transcriptional mechanism. Melatonin but not tryptophan or serotonin inhibited lipopolysaccharide (LPS)-induced COX-2 and iNOS protein levels and promoter activities in RAW 264.7 cells in a time- and concentration-dependent manner. LPS or LPS plus interferon-gamma (IFN gamma) increased binding of all 5 isoforms of NF-kappa B to COX-2 and iNOS promoters. Melatonin selectively inhibited p52 binding without affecting p100 expression, p52 generation from p100, or p52 nuclear translocation. p52 acetylation was enhanced by LPS, which was abrogated by melatonin. Melatonin inhibited p300 histone acetyltransferase (HAT) activity and abrogated p300-augmented COX-2 and iNOS expression. HAT inhibitors suppressed LPS-induced p52 binding and acetylation to an extent similar to melatonin, and melatonin did not potentiate the effect of HAT inhibitors. These results suggest that melatonin inhibits COX-2 and iNOS transcriptional activation by inhibiting p300 HAT activity, thereby suppressing p52 acetylation, binding, and transactivation.