Integrin-mediated signals play an important but poorly understood role in regulating many leucocyte functions. In monocytes and macrophages, integrins of the β2 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, β1 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 β1 or β2 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 κB (NF-κB) activation was also detected in THP-1 cells transiently transfected with an NF-κB-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-β1 antibodies caused activation of ERK while that by anti-β2 antibodies did not. Also both types of integrin activated NF-κB. However, PI-3K was required for β1 integrin-, but not β2 integrin-, mediated NF-κB activation. In addition, inhibition of PI-3K with wortmannin and LY294002 blocked β1 integrin-mediated NF-κB activation, but did not affect that mediated by β2 integrin. These data suggest that distinct integrins activate different signalling pathways in monocytic cells.
- phosphoinositide 3-kinase
- signal transduction
Abbreviations used: ECM, extracellular matrix; ERK, extracellular signal-regulated kinase; pERK, activated phospho-ERK; MEK, ERK kinase; PI-3K, phosphoinositide 3-kinase; NF-κB, nuclear factor κB; ICAM, intercellular cell-adhesion molecule; IL, interleukin; TNFα, tumour necrosis factor α.
- The Biochemical Society, London ©2002