GRO family chemokines are specialized for monocyte arrest from flow

Abstract

Chemokines participate in various processes of monocyte recruitment including monocyte arrest and migration. Our group and others have demonstrated that growth-related oncogene (GRO)-alpha (CXCL1) can support monocyte arrest in models of inflammation. Here we employed a parallel plate-flow chamber and Transwell reconstitution assay to test whether GRO family chemokines were sufficient for Mono Mac 6 (a human monocytic cell line) and isolated human monocyte recruitment. Our study shows that 1) GRO-alpha, -beta (CXCL2), and -gamma (CXCL3) all act as arrest chemokines for monocyte adhesion on vascular cell adhesion molecule (VCAM)-1 under flow in the presence of P-selectin; 2) CXCR2 is the functional receptor for GRO-family chemokines in monocyte arrest; however, CXCR2 is not an arrest chemokine receptor in general, since epithelial neutrophil-activating peptide ENA-78 failed to arrest monocytes; 3) GRO-alpha, -beta, and -gamma all fail to increase intracellular free Ca2+ or mediate monocyte chemotaxis; and 4) signaling through G alpha(i) protein, phosphoinositide 3-kinase, and actin polymerization but not Ca2+ mobilization or the mitogen-activated kinases p38 and MAPK/extracellular signal-related kinase are necessary for GRO-alpha-mediated Mono Mac 6 cell arrest under flow. We conclude that the GRO-family chemokines are specialized monocyte-arrest chemokines. Their role in monocyte recruitment in inflammation can be inhibited by blocking CXCR2 function or downstream signaling events.