Activation Of Integrin LFA-1and IL-8-Mediated Cell Adhesion Under Flows

Leukocytes migration to sites of injury or inflammation is an important part of ourimmune system. During this process, the adhesion receptor family is required, especially theintegrin, which mediates firm adhesion to endothelium and transmigration to inflammationsites.The integrin LFA-1(Lymphocyte function-associated antigen-1) induced by metal ions iscrucial to immune response. Only when LFA-1induced by the magnesium tointermediate-affinity, and interacts with its ligand ICAM-1(Intercellular Adhesion Molecule-1)under the force, then the outside-in signaling pathway can be opened. By comparison of theresults obtained from the flow chamber experiment and affinity transitions model, the kineticdynamics behavior was obtained.The experimental results demonstrate that the complex (LFA-1/ICAM-1) can transitfrom intermediate-affinity state to high-affinity state under the force. And both of the twostates show that within the range of wall shear stress0.025dyn/cm2-0.045dyn/cm2(ss0.025dyn/cm2-ss0.045dyn/cm2), as the increasing of the wall shear stress, the off-rate of thecomplex is increasing gradually. However, when the force is within the range ofss0.045dyn/cm2-ss0.06dyn/cm2, the increasing of force will slow down the Off-rate.Furthermore, when the force is within the range of ss0.06dyn/cm2-ss0.1dyn/cm2, the off-ratestarts to rise back up. By establishing a kinetic model, we get the transition rate of differentcomplexes. Our results indicate that the transition rate maintains at0.3during ss0.025dyn/cm2-ss0.05dyn/cm2, when the force reaches ss0.06dyn/cm2, it increases to1.6. Forcehas important regulatory effects during the transition. Like LFA-1/ICAM-1, the interactionbetween chemokine IL-8and its recptors is regulated by force as well.The kinetic parameters measured allow us to better understand the molecularmechanisms of LFA-1/ICMA-1, and the immune responses of leukocytes in inflammation,thrombosis and other physiological process. The work aims to provide useful information andnew ideas for new drugs design and new treatment on related diseases.