FcγRIIIB stimulation promotes β1 integrin activation in human neutrophils

The molecular stimuli involved in receptor-induced integrin activation are still poorly defined. We have investigated the role of receptors for the Fc portion of immunoglobulin G molecules (FcγR) on activation of integrins in human neutrophils. Cross-linking of FcγRIIA induced an increase in surface expression of β2 integrins but had no effect on β1 integrins. In contrast, cross-linking of FcγRIIIB not only increased β2 integrins on the cell surface but also induced β1 integrin activation, as indicated by an increase in binding to fibronectin and the appearance of an activation epitope detected by the monoclonal antibody 15/7. The FcγRIIIB-induced increase of β2 integrins required Src-family tyrosine kinases, Syk kinase, and phosphatidylinositol-3 kinase (PI-3K), as the corresponding, specific inhibitors, PP2, Piceatannol, and LY294002, completely blocked it. Contrary to this, FcγRIIIB-indued β1 integrin activation was not blocked by PP2 or LY294002. It was, however, enhanced by Piceatannol. After FcγRIIIB cross-linking, colocalization of FcγRIIIB and active β1 integrins was detected on the neutrophil membrane. These data show, for the first time, that cross-linking of FcγRIIIB induces an inside-out signaling pathway that leads to β1 integrin activation. This activation is independent of Src-family kinases, and PI-3K and may be induced in part by the interaction of FcγRIIIB with β1 integrins.