Abstract
Integrin-mediated signals play an important but poorly understood role in regulating many leucocyte functions. In monocytes and macrophages, integrins of the beta2 subfamily are involved in cell-cell interactions that are important for migration of the cells through the endothelium and also for phagocytosis. On the other hand, in the same cells, beta1 integrin-mediated adhesion to extracellular matrix proteins results in a strong induction of immediate early genes that are important in inflammation. To investigate the signalling pathways from these two types of integrin in monocytic cells, THP-1 cells were selectively stimulated via beta1 or beta2 integrins by cross-linking each type of receptor with specific monoclonal antibodies or their natural ligands. The involvement of extracellular signal-regulated kinase (ERK), Syk and phosphoinositide 3-kinase (PI-3K) was then analysed. Nuclear factor kappaB (NF-kappaB) activation was also detected in THP-1 cells transiently transfected with an NF-kappaB-driven luciferase reporter gene. We found that binding of both types of integrin to their natural ligands activated ERK in a Syk- and PI-3K-dependent manner. Yet, cross-linking of integrins by anti-beta1 antibodies caused activation of ERK while that by anti-beta2 antibodies did not. Also both types of integrin activated NF-kappaB. However, PI-3K was required for beta1 integrin-, but not beta2 integrin-, mediated NF-kappaB activation. In addition, inhibition of PI-3K with wortmannin and LY294002 blocked beta1 integrin-mediated NF-kappaB activation, but did not affect that mediated by beta2 integrin. These data suggest that distinct integrins activate different signalling pathways in monocytic cells.