力诱导循环血流中白细胞整合素LFA-1的激活机制  

Mechanism of force-induced activation of integrin LFA-1 under circulating flows

作　　者：童洁[1] 刘黎[1] 吴建华[1] 方颖[1] 

机构地区：[1]华南理工大学生物科学与工程学院,生物力学研究所,广州510006

出　　处：《医用生物力学》2015年第1期14-20,共7页Journal of Medical Biomechanics

基　　金：国家自然科学基金资助项目(11272125;31170887)

摘　　要：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 mPa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 reveal the mechanical regulation mechanism for activation of lymphocyte function-associated antigen 1（ LFA-1）. Methods The LFA-1 expressed on Jurkat cell surface was pre-activated by Mg2 ＋from quiescent-to intermediate-affinity state,and the tether events of Jurkat cells under different wall shear stresses（ 4. 5-10 mPa） were observed and analyzed by flow chamber experiment. Meanwhile,a probabilistic model of integrin affinity jumping was established. Results The affinity jumping model was well fitted with the data obtained from flow chamber experiment. Under flowing loads,LFA-1 from intermediate to high-affinity state was observed,with prolonging of the adhesion bonds. The probability of tether event was 15%-26%. LFA-1 at high-affinity state contributed a significant fraction（ about 26%-40%） of the bond lifetime. The off-rate of LFA-1 at high-affinity state was slower by 19%-65% as compared to that at intermediate-affinity state. Dissociating of ICAM-1 from LFA-1was force-dependent and governed either by slip-bond at intermediate-affinity state or by catch-slip bond at highaffinity state. Conclusions The force-induced activation of LFA-1 mediates the slower rolling and firm adhesion of the cells. This research finding will further the understanding of inflammatory response events of circulating leukocytes,and contribute to the discovery of new antibody drug targets for the associated diseases.

关 键 词：白细胞整合素 整合素激活 受体配体相互作用 细胞黏附 

分 类 号：R318.01[医药卫生—生物医学工程]