LFA-1 integrin antibodies inhibit leukocyte alpha(4)beta(1)-mediated adhesion by intracellular signaling

摘要

Bindingof intercellular adhesionmolecule-1 to the beta(2)-integrin leukocyte function associated antigen-1 (LFA-1) is known to induce cross-talk to the alpha(4)beta(1) integrin. Using different LFA-1 monoclonal antibodies, we have been able to study the requirement and mechanism of action for the cross-talk in considerable detail. LFA-1-activating antibodies and those inhibitory antibodies that signal to alpha(4)beta(1) induce phosphorylation of Thr-758 on the beta(2)-chain, which is followed by binding of 14-3-3 proteins and signaling through the G protein exchange factor Tiam1. This results in dephosphorylation of Thr-788/789 on the beta(1)-chain of alpha(4)beta(1) and loss of binding to its ligand vascular cell adhesion molecule-1. The results show that with LFA-1 antibodies, we can activate LFA-1 and inhibit alpha(4)beta(1), inhibit both LFA-1 and alpha(4)beta(1), inhibit LFA-1 but not alpha(4)beta(1), or not affect LFA-1 or alpha(4)beta(1). These findings are important for the understanding of integrin regulation and for the interpretation of the effect of integrin antibodies and their use in clinical applications.