Selenium supplementation induces metalloproteinase-dependent L-selectin shedding from monocytes
Selenium supplementation induces metalloproteinase-dependent L-selectin shedding from monocytes
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DOI：
10.1189/jlb.0707497
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发表时间：
2008-06-01
影响因子：
5.5
通讯作者：
Peter, Karlheinz
中科院分区：
文献类型：
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作者：
Ahrens, Ingo;Ellwanger, Christoph;Peter, Karlheinz
严重脓毒症患者的硒治疗可改善临床结局，并与硒蛋白谷胱甘肽过氧化物酶活性增加有关。然而，观察到的有益效果的机制仍不清楚。我们确定了硒治疗对单核细胞粘附分子L-选择素和L-选择素相关的单核细胞功能的影响，并将我们的发现转移到体内小鼠模型中。纯化单核细胞，培养，并在存在或不存在补充硒和金属蛋白酶（MP）抑制剂的情况下孵育长达16小时。在硒存在下孵育2和6小时后，L-选择素的表达不受影响，但在16小时后下降。用ELISA法测定上清液中可溶性L-选择素（sL-选择素）。硒处理16小时后，观察到L-选择素脱落导致的2.3倍增加。添加MP抑制剂GM 6001、TNF-α转化酶抑制剂2或GW 280264 X强烈减少硒诱导的L-选择素脱落，表明MP依赖性机制。在流动室模型中检查L-选择素脱落的功能后果。硒处理的单核细胞在静脉剪切应力（0.5达因/厘米2）条件下显示出显著降低的滚动和对L-选择素配体Sialyl-Lewisa的粘附。硒治疗C57 BL 6小鼠导致血清中的sL-选择素水平增加，强调了我们的研究结果在体内的相关性。我们描述了一个硒诱导的下调单核细胞上的L-选择素作为一个结果的MP依赖性脱落这种膜锚定的粘附分子。补充硒对单核细胞粘附的损害可能是严重脓毒症患者炎症反应调节的一个重要的潜在机制。
Selenium therapy in patients with severe sepsis improves clinical outcome and has been associated with increased activity of the selenoprotein glutathione peroxidase. However, the mechanism of the observed beneficial effects remains unclear. We determined the effect of selenium treatment on the monocyte adhesion molecule L-selectin and L-selectin-related monocyte functions in vitro and transferred our findings to an in vivo mouse model. Monocytes were purified, cultured, and incubated in the presence or absence of supplemented selenium and metalloproteinase ( MP) inhibitors for up to 16 h. Expression of L-selectin was unaffected after 2 and 6 h but decreased after 16 h of incubation in the presence of selenium. Soluble L-selectin (sL-selectin) in the supernatant was determined by ELISA. A 2.3-fold increase as a result of shedding of L-selectin was observed after 16 h of selenium treatment. Addition of the MP inhibitors GM6001, TNF-alpha-converting enzyme inhibitor 2, or GW280264X strongly reduced selenium-induced L-selectin shedding, indicating a MP-dependent mechanism. The functional consequences of L-selectin shedding were examined in a flow chamber model. Selenium-treated monocytes showed significantly decreased rolling and adhesion to the L-selectin ligand Sialyl-Lewisa under conditions of venous shear stress (0.5 dyne/cm(2)). Selenium treatment of C57BL6 mice led to increased serum levels of sL-selectin, underscoring the in vivo relevance of our findings. We describe a selenium-induced down-regulation of L-selectin on monocytes as a consequence of MP-dependent shedding of this membrane-anchored adhesion molecule. The impairment of monocyte adhesion by selenium supplementation may represent an important, underlying mechanism for the modulation of inflammatory reactions in patients with severe sepsis.