Identification of potent small-molecule inhibitors of STAT3 with anti-inflammatory properties in RAW 264.7 macrophages.
Identification of potent small-molecule inhibitors of STAT3 with anti-inflammatory properties in RAW 264.7 macrophages.
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DOI：
10.1111/j.1742-4658.2012.08739.x
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发表时间：
2012-10
期刊：
影响因子：
--
通讯作者：
Marambaud P
中科院分区：
文献类型：
--
作者：
Capiralla H;Vingtdeux V;Venkatesh J;Dreses-Werringloer U;Zhao H;Davies P;Marambaud P
信号转导子和转录激活子3（STAT 3）是巨噬细胞和其他免疫细胞类型的炎症反应的关键介导物。天然存在的多酚白藜芦醇通过涉及抑制STAT 3信号传导的机制与抗增殖和抗炎特性相关。在这里，我们报告了白藜芦醇的小分子类似物RSVA 314和RSVA 405是STAT 3的有效抑制剂。RSVA 314和RSVA 405分别抑制HEK 293细胞和脂多糖（LPS）激活的RAW 264.7巨噬细胞中的组成型和刺激型STAT 3。这些小分子类似物对STAT 3的抑制作用比白藜芦醇强近50倍（表观IC 50 ~ 0.5 μM）。我们进一步表明RSVA 405通过抑制IKK和IκBα磷酸化以及通过降低几种细胞因子的表达，包括NF-κB靶基因、肿瘤坏死因子-α和白细胞介素-6，来干扰LPS刺激后RAW 264.7细胞的炎症反应。LPS刺激后STAT 1的下游活化也被RSVA 405抑制。因此，RSVA 405显著干扰LPS激活的RAW 264.7巨噬细胞的吞噬活性和增殖。最后，我们发现两种小分子类似物对STAT 3磷酸化的影响可以被蛋白酪氨酸磷酸酶（PTPs）抑制剂阻止，表明小分子通过促进PTPs对STAT 3的去磷酸化而起作用。
Signal transducer and activator of transcription 3 (STAT3) is a key mediator of the inflammatory response by macrophages and other immune cell types. The naturally occurring polyphenol resveratrol is associated with anti-proliferative and anti-inflammatory properties via mechanisms implicating inhibition of STAT3 signaling. Here, we report that the small-molecule analogs of resveratrol, RSVA314 and RSVA405, are potent inhibitors of STAT3. RSVA314 and RSVA405 inhibited both constitutive and stimulated STAT3 in HEK293 cells and lipopolysaccharide (LPS)-activated RAW 264.7 macrophages, respectively. The small-molecule analogs inhibited STAT3 nearly 50 times more potently than did resveratrol (apparent IC50 ~ 0.5 μM). We further show that RSVA405 interfered with the inflammatory response by RAW 264.7 cells upon LPS stimulation by inhibiting IKK and IκBα phosphorylation and by decreasing the expression of several cytokines, including the NF-κB target genes, tumor necrosis factor-α and interleukin-6. Downstream activation of STAT1 upon LPS stimulation was also inhibited by RSVA405. Consequently, RSVA405 significantly interfered with the phagocytotic activity and proliferation of LPS-activated RAW 264.7 macrophages. Finally, we found that the effect of the two small-molecule analogs on STAT3 phosphorylation could be prevented by inhibitors of protein tyrosine phosphatases (PTPs), indicating that the small-molecules acted by promoting the dephosphorylation of STAT3 by PTPs.
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影响因子：
5.7
作者：
Vingtdeux, Valerie;Chandakkar, Pallavi;Marambaud, Philippe
通讯作者：
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影响因子：
1.8
作者：
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影响因子：
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作者：
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影响因子：
2.4
作者：
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通讯作者：
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影响因子：
4
作者：
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通讯作者：
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