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Regulation of Interleukin-5–Induced ß₂-Integrin Adhesion of Human Eosinophils by Phosphoinositide 3-Kinase

Section of Pulmonary and Critical Care Medicine, Department of Medicine; and Department of Neurobiology Pharmacology and Physiology and Committees on Molecular Medicine, Clinical Pharmacology, and Cell Physiology, University of Chicago, Chicago, Illinois

Correspondence and requests for reprints should be addressed to Dr. Alan R. Leff, Section of Pulmonary and Critical Care Medicine, Department of Medicine, MC6076, University of Chicago, 5841 South Maryland Avenue, Chicago, IL 60637. E-mail address: aleff{at}medicine.bsd.uchicago.edu

We examined the role of phosphoinositide 3-kinase (PI3K) in integrin-mediated eosinophil adhesion. p85, a dominant-negative form of the class IA PI3K adaptor subunit, was fused to an HIV-TAT protein transduction domain (TAT-p85). Recombinant TAT-p85 inhibited interleukin (IL)-5–stimulated phosphorylation of protein kinase B, a downstream target of PI3K. ß₂-Integrin–dependent adhesion caused by IL-5 to the plated intracellular adhesion molecule-1 surrogate, bovine serum albumin, was inhibited by TAT-p85 in a concentration-dependent manner. Similarly, two PI3K inhibitors, wortmannin and LY294002, blocked eosinophil adhesion to plated bovine serum albumin. By contrast, ß₁-integrin–mediated eosinophil adhesion to vascular cell adhesion moelcule-1 was not blocked by TAT-p85, wortmannin, or LY294002. Rottlerin, a protein kinase C (PKC)- inhibitor, also blocked ß₂-integrin adhesion of eosinophils caused by IL-5, whereas ß₁ adhesion to vascular cell adhesion molecule-1 was not affected. IL-5 caused translocation of PKC from the cytosol to cell membrane; inhibition of PI3K by wortmannin blocked translocation of PKC. Western blot analysis demonstrated that extracellular signal–regulated kinase phosphorylation, a critical intermediary in adhesion elicited by IL-5, was blocked by inhibition of either PI3K or PKC-. These data suggest that extracellular signal–regulated kinase–mediated adhesion of ß₂-integrin caused by IL-5 is mediated in human eosinophils by a class IA PI3K through activation of a PKC pathway.

Key Words: phosphoinositide 3-kinase • eosinophil • adhesion

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