The p110δ Isoform of PI3K Differentially Regulates β1 and β2 Integrin-Mediated Monocyte Adhesion and Spreading and Modulates Diapedesis

Objective: Leukocyte diapedesis is misregulated in inflammatory disease and depends on the binding of monocytic LFA-1 and VLA-4 to endothelial ICAM-1 and VCAM-1, respectively. The authors hypothesized that these different molecular interactions elicit specific signaling cascades within monocytes regulating specific steps in adhesion, motility, and diapedesis.Methods: The authors employed the PI3K p110δ catalytic subunit specific inhibitor IC87114 (2 μ M) and the broad-spectrum PI3K inhibitory agents LY294002 (50 μ M) and wortmannin (100 nM), to examine the role of PI3Kδ in monocyte diapedesis through endothelial monolayers and its role in monocyte adhesion and spreading upon carpets of ICAM-1 or VCAM-1. They further explored the effects of PI3Kδ inhibition on the activation state of β 1 and β 2 integrins with immunocytochemistry and flow cytometry.Results: In human peripheral blood monocytes IC87114 was as effective as wortmannin and LY294002 at inhibiting diapedesis, however, in THP-1 cells LY294002 and ...