Ligand binding to monocyte α₅β₁ integrin activates the α₂β₁ receptor via the α₅ subunit cytoplasmic domain and protein kinase C¹

Regulation of the functional status of integrin receptors plays a critical role in inflammation and tissue remodeling, as it affects cell adherence and cytokine secretion. We have previously shown that in monocytes the binding of collagen to the α₂β₁ integrin induces the release of IL-1, an event that is potentiated by binding of fibronectin (Fn) to the α₅β₁ integrin. In this study, we have investigated the mechanisms leading to this phenomenon. Fn binding to α₅β₁ induced intracellular signals which increased the α₂β₁-dependent adhesiveness of monocytes to collagen without modifications of α₂β₁ expression. By using Abs against the intracellular region of the α₅ subunit of the α₅β₁ receptor, and specific inhibitors of protein kinase C (PKC), we found that the potentiation effect of Fn on monocyte IL-1 production and their adherence to collagen was dependent on an intact α₅ subunit cytoplasmic domain, and required PKC activation. Although the α₂β₁ could be activated by several intracellular second messengers, including protein kinase A and intracellular calcium, the potentiating effect of Fn was mediated only by PKC. These data provide an example of a novel regulatory mechanism: potentiation of β₁ integrin-mediated events as a result of ligand binding to another integrin of the same class. They also show that the intracellular region of α₅β₁ plays a critical role in transducing signals generated by ligand binding to α₅β₁.