Differential Regulation of Chemoattractant-Stimulated β2, β3, and β7 Integrin Activity

Abstract

Leukocyte adhesion to endothelium and extravasation are dynamic processes that require activation of integrins. Chemoattractants such as IL-8 and FMLP are potent activators of leukocyte integrins. To compare the chemoattractant-stimulated activation of three integrins, α4β7, αLβ2, and αVβ3, in the same cellular context, we expressed an IL-8 receptor (IL-8RA) and FMLP receptor (FPR) in the lymphoid cell line JY. Chemoattractants induced a rapid increase in αLβ2- and αVβ3-dependent JY adhesion within 5 min, and it was sustained for 30 min. In contrast, stimulation of α4β7-dependent adhesion was transient, returning to basal levels by 30 min. The activation profiles of the integrins were similar regardless of whether IL-8 or FMLP was used for induction. We also demonstrate that α4β7-dependent adhesion was uniquely responsive to the F actin-disrupting agent cytochalasin D and the protein kinase C (PKC) inhibitor chelerythrin. While αVβ3- and αLβ2-mediated cell adhesion was significantly reduced by cytochalasin D, α4β7-mediated adhesion was enhanced. Chelerythrin inhibited both the IL-8 and PMA activation of αLβ2 and αVβ3. In contrast, inducible α4β7 activity was unaffected, and basal activity was increased. These findings demonstrate that the mechanism of α4β7 regulation by chemoattractants is different from that of αLβ2 and αVβ3 and that it appears to involve distinct cytoskeletal and PKC dependencies. In addition, PKC activity may be a positive or negative regulator of integrin-dependent adhesion.