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目的探讨白细胞整合素LFA-1活化的力学调控机制。方法利用Mg2+将LFA-1从静息态趋化为中等亲和态,并结合流动腔实验,在4.5~10 m Pa流体壁面剪应力条件下,观察分析LFA-1介导的Jurkat细胞拴缚事件;同时建立整合素亲和态跃迁概率模型。结果理论模型可以很好地拟合流动腔实验数据。在拉力作用下,LFA-1的亲和态将发生从中到高的跃迁,导致黏附分子键的延长;细胞拴缚事件的发生概率为15%~26%,LFA-1在键存续时间的后26%~40%时段内将处于高亲和态;相较于中等亲和态而言,高亲和态LFA-1的解离速率要慢19%~65%,两者均呈现力依赖性,前者受逆锁键调控,后者涉及逆锁键到滑移键的转换。结论力通过诱导循环血流中LFA-1的激活介导白细胞的慢速滚动和稳定黏附。这一力诱导的LFA-1激活过程,将加深对循环白细胞炎症响应事件的理解,并促进相关疾病抗体药物靶标的发现。
Objective To investigate the mechanistic mechanism of LFA-1 activation. Methods LFA-1 was chemotaxis from resting state to medium affinity state by using Mg2 +, and in combination with flow chamber experiments, LFA-1-mediated Jurkat cell tethering was observed and analyzed under fluid wall shear stress of 4.5-10 mPa Events; at the same time, establish the prokaryotic affinity state transition probability model. The theoretical model can well fit the experiment data of flow cavity. Under the action of tension, the LFA-1 affinity state will shift from the middle to the high, leading to the prolongation of the adhesion molecule bond. The probability of cell tethering event is 15% -26% 26% ~ 40% of the time period will be in a high affinity state; compared to the intermediate affinity state, high affinity LFA-1 dissociation rate slow 19% to 65%, both were in a force-dependent manner , The former by the inverse lock key regulation, which involves the reverse key to the slip key conversion. CONCLUSION: L980-induced activation of LFA-1 induces leukocyte slow rolling and stable adhesion. This force-induced LFA-1 activation process will deepen the understanding of circulating leukocyte inflammatory response events and facilitate the discovery of drug-related targets for drug targets.