Influence of the fungal NF-κB inhibitor panepoxydone on inflammatory gene expression in MonoMac6 cells
Influence of the fungal NF-κB inhibitor panepoxydone on inflammatory gene expression in MonoMac6 cells
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DOI：
10.1016/j.intimp.2007.01.001
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发表时间：
2007-05-01
影响因子：
5.6
通讯作者：
Anke, T.
中科院分区：
文献类型：
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作者：
Erkel, G.;Wisser, G.;Anke, T.
真菌次生代谢物帕环氧酮最近被描述为核因子-kappaB激活的抑制剂，核因子-kappaB是炎症和免疫反应的关键调节因子。这些发现表明，帕环氧酮可能是一种有用的抗炎药。在本研究中，我们首次研究了帕环氧酮对脂多糖(LPS)和佛波酯(TPA)刺激的单核细胞系MonoMac6中炎性基因表达的影响。对110个已知在炎症过程中受到强烈调控的人类基因的DNA微阵列分析，结合逆转录实时定量聚合酶链式反应(RT-qPCR)显示，低微摩尔浓度(12-24 MU)的帕环氧酮强烈抑制33个依赖NF-kappa B的促炎基因的表达，例如趋化因子CCL3、CCL4、CCL8；CXCL8、CXCL10、CXCL20；细胞因子IL-1、IL-6、TNF-α、促炎酶COX-2，以及rel/NF/kappa B/I kappa B家族的成员，但对管家基因的表达没有显著影响。在LPS/TPA刺激的MonoMac6细胞中，帕环氧酮通过阻断I-kappa B的磷酸化和随后激活的核因子-k13转录因子与DNA的结合而强烈抑制hTNF-α、IL-8和NF-kappaB启动子的活性，IC50值为0.5-1mUg/ml。从我们的数据来看，帕环氧酮可能是开发基于转录的促炎基因表达抑制物的先导结构。(C)2007 Elsevier B.V.保留所有权利。
The fungal secondary metabolite panepoxydone has been recently described as an inhibitor of NF-kappa B activation which is a pivotal regulator of the inflammatory and immune response. These findings have led to propose that panepoxydone may be useful as anti-inflammatory agent. In this study we investigated for the first time the effects of panepoxydone on inflammatory gene expression in the monocytic cell line MonoMac6, stimulated with lipopolysaccharide (LPS) and the phorbolester 12-Otetradecanoylphorbol -13-acetate (TPA). DNA microarray analysis of 110 human genes known to be strongly regulated during inflammation, combined with reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) revealed that low micromolar concentrations (12-24 mu M) of panepoxydone strongly inhibited the expression of thirty-three NF-kappa B dependent pro-inflammatory genes such as the chemokines CCL3, CCL4, CCL8; CXCL8, CXCL10, CXCL20, the cytokines IL-1, IL-6, TNF-alpha, pro-inflammatory enzymes like COX-2, and components of the REL/NF/kappa B/I kappa B family without significant effects on the expression of house-keeping genes. Panepoxydone strongly inhibited hTNF-alpha, IL-8 and NF-kappa B promoter activity in LPS/TPA stimulated MonoMac6 cells with IC50 values of 0.5-1 mu g/ml by blocking the phosphorylation of I kappa B and subsequent binding of the activated NF-K13 transcription factor to the DNA. From our data, panepoxydone may serve as lead structure for the development of transcription-based inhibitors of pro-inflammatory gene expression. (c) 2007 Elsevier B.V. All rights reserved.