Tamoxifen augments the innate immune function of neutrophils through modulation of intracellular ceramide.
Tamoxifen augments the innate immune function of neutrophils through modulation of intracellular ceramide.
复制标题
他莫昔芬通过调节细胞内神经酰胺来增强中性粒细胞的先天免疫功能。
DOI：
10.1038/ncomms9369
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发表时间：
2015-10-13
影响因子：
16.6
通讯作者：
Nizet V
中科院分区：
文献类型：
--
作者：
Corriden R;Hollands A;Olson J;Derieux J;Lopez J;Chang JT;Gonzalez DJ;Nizet V
他莫昔芬是一种选择性雌激素受体调节剂，广泛用于治疗乳腺癌。除了其作为雌激素受体激动剂/拮抗剂的活性外，他莫昔芬还调节鞘脂生物合成，这已被证明在中性粒细胞活性的调节中起重要作用。在这里，我们发现，他莫昔芬刺激增强人中性粒细胞，包括趋化性，吞噬作用和中性粒细胞胞外陷阱（NET）的形成几个促炎途径。NET产生的增强通过神经酰胺/PKC β介导的途径发生，并且用合成神经酰胺处理足以促进NET形成。用他莫昔芬预处理人中性粒细胞可增强中性粒细胞体外对多种病原体的杀菌能力，并增强体内对主要人类病原体耐甲氧西林金黄色葡萄球菌的清除。我们的研究结果表明，他莫昔芬，和它调节的脂质信号通路，值得进一步探索作为目标，以提高宿主的先天免疫功能。
Tamoxifen is a selective estrogen receptor modulator widely used for the treatment of breast cancer. In addition to its activity as an estrogen receptor agonist/antagonist, tamoxifen also modulates sphingolipid biosynthesis, which has been shown to play an important role in the regulation of neutrophil activity. Here, we find that tamoxifen stimulation enhances several pro-inflammatory pathways in human neutrophils, including chemotaxis, phagocytosis and neutrophil extracellular trap (NET) formation. The enhancement of NET production occurs via a ceramide/PKCζ-mediated pathway, and treatment with synthetic ceramide is sufficient to promote NET formation. Pretreatment of human neutrophils with tamoxifen boosts neutrophil bactericidal capacity against a variety of pathogens in vitro and enhances clearance of the leading human pathogen methicillin-resistant Staphylococcus aureus in vivo. Our results suggest that tamoxifen, and the lipid signaling pathways it modulates, merit further exploration as targets for boosting host innate immune function.