β1 and β2 integrins activate different signalling pathways in monocytes

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.

Activation of NF-κB by Extracellular Matrix Is Involved in Spreading and Glucose-stimulated Insulin Secretion of Pancreatic Beta Cells

“…Several different signaling proteins have been reported to mediate signaling from ECM to NF-B, including MAP kinase ERK (37), PI3K (5,10), and Rho GTPase Rac (5,10,38). We have reported previously (4) that the MAP kinase-ERK and PI3K-Akt/PKB pathways are activated by 804G-ECM, suggesting that these latter pathways might be involved in 804G-ECM-induced NF-B activity.…”

Analysis of Cell Migration within a Three-dimensional Collagen Matrix

“…Likewise, cells exhibit various integrin molecules recognizing different extracellular matrix components, which may result in the activation of different signal transduction cascades 45 concomitant with a differential outcome. For instance, β1-integrin stimulation caused activation of ERK in monocytes while β2-stimulation did not 46 . Likewise, PI3K was required for β1-integrin-, but not β2-integrin-, mediated NF-κB activation 46 .…”

“…For instance, β1-integrin stimulation caused activation of ERK in monocytes while β2-stimulation did not 46 . Likewise, PI3K was required for β1-integrin-, but not β2-integrin-, mediated NF-κB activation 46 . On the other hand, collagen type I is the most abundant collagen in the human body 47 suggesting that the migration of cells is chiefly triggered by this collagen type.…”

Regulation of p21-activated Kinase-independent Rac1 Signal Transduction by Nischarin

“…Integrins signal to NF-B through phosphatidylinositol 3-kinase and Rac1 (34). Rac1, as well as Cdc42 and RhoA, can stimulate the phosphorylation of IB, an inhibitor of NF-B function, leading to its degradation and NF-B activation (35,36).…”