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Differential Regulation of Chemoattractant-Stimulated ß₂, ß₃, and ß₇ Integrin Activity

ICOS Corporation, Bothell, WA 98021

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, ₄ß₇, _Lß₂, and _Vß₃, 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 _Lß₂- and _Vß₃-dependent JY adhesion within 5 min, and it was sustained for 30 min. In contrast, stimulation of ₄ß₇-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 ₄ß₇-dependent adhesion was uniquely responsive to the F actin-disrupting agent cytochalasin D and the protein kinase C (PKC) inhibitor chelerythrin. While _Vß₃- and _Lß₂-mediated cell adhesion was significantly reduced by cytochalasin D, ₄ß₇-mediated adhesion was enhanced. Chelerythrin inhibited both the IL-8 and PMA activation of _Lß₂ and _Vß₃. In contrast, inducible ₄ß₇ activity was unaffected, and basal activity was increased. These findings demonstrate that the mechanism of ₄ß₇ regulation by chemoattractants is different from that of _Lß₂ and _Vß₃ 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.

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