Abstract
Positive regulation of cell migration by chemotactic factors and downstream signaling pathways has been extensively investigated. In contrast, little is known about factors and mechanisms that induce migration arrest, a process important for retention of cells at inflammatory sites and homeostatic regulation of cell trafficking. In this study, we found that IFN-gamma directly inhibited monocyte migration by suppressing remodeling of the actin cytoskeleton and cell polarization in response to the chemokine CCL2. Inhibition was dependent on STAT1 and downstream genes, whereas STAT3 promoted migration. IFN-gamma altered monocyte responses to CCL2 by modulating the activity of Pyk2, JNK, and the GTPases Rac and Cdc42, and inhibiting CCL2-induced activation of the downstream p21-activated kinase that regulates the cytoskeleton and cell polarization. These results identify a new role for IFN-gamma in arresting monocyte chemotaxis by a mechanism that involves modulation of cytoskeleton remodeling. Crosstalk between Jak-STAT and Rac/Cdc42 GTPase-mediated signaling pathways provides a molecular mechanism by which cytokines can regulate cell migration.
Highlights
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IFN-␥ suppresses trafficking of myeloid cells in vivo, it is not known whether IFN-␥ directly inhibits the motility and chemotaxis of monocytes in addition to indirect regulation of chemokine production and endothelial cell function
We found that IFN-␥ directly inhibits chemokine-induced monocyte migration by mechanisms that involve decreased remodeling of the actin cytoskeleton and an associated block in monocyte polarization toward a chemotactic gradient
Summary
The preponderance of the evidence suggests that inhibition of myeloid cell migration by IFN-␥ in vivo serves a homeostatic function in limiting infiltration of inflamed tissues and controlling associated tissue damage (13, 16 –24). IFN-␥ worked by suppressing monocyte polarization in response to CCL2 and the underlying mechanism was altered regulation of actin polymerization and Rac/Cdc42PAK signaling pathways that are important for migration. These results identify a new role for IFN-␥ and the Jak-STAT pathway in regulating monocyte chemotaxis, and provide a mechanism by which previously unappreciated crossregulation between Jak-STAT and small GTPase signaling pathways regulates cell migration
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