Regulation of the very late antigen-4-mediated adhesive activity of normaland nonreleaser basophils: roles for Src, Syk, and phosphatidylinositol 3-kinase

Normal human basophils express the integrin, VLA-4, and cross-linking their high-affinity IgE receptor, Fc epsilon RI, increases their VLA-4-dependent adhesion to VCAM-1-transfected Chinese hamster ovary (CHO) cells. Here we show that the Fc epsilon RI-mediated up-regulation of normal basophil VLA-4 adhesion is abolished by the Src inhibitor, PP1, the Syk inhibitor, ER-273 19, and the phosphatidylinositol 3-kinase inhibitor, wortmannin. PP1, but n ot ER-27319 or wortmannin, also reduces basal adhesion and adhesion stimula ted by chemotactic peptide, by Ca++ ionophores, and by phorbol myristate ac etate (PMA). Nonreleaser basophils (the consistently Syk-deficient, variabl y Lyn-deficient, severely degranulation-impaired cells found in about 10% o f donors) share the PP1 phenotype of lowered basal adhesion, no Fc epsilon RI-mediated adhesion up-regulation, and reduced adhesive responses to chemo attractant ionophores and PMA. These results implicate Src kinases in the c ontrol of basal VLA-4 activity and place Syk and phosphatidylinositol 3-kin ase in the pathway linking Fc epsilon RI cross-linking to VLA-4 up-regulati on. Both Src and Syk-regulated components of adhesion may be impaired in no nreleaser basophils.