Objective Monocyte recruitment by proinflammatory cytokines is a hallmark of rheumatoid arthritis (RA). Lewis y-6 and H (Le y /H) are blood group antigens up-regulated on RA synovial endothelium. We have previously shown that both soluble Le y /H and a glucose analog of H, H-2g, are angiogenic and mediateleukocyte–endothelial adhesion via induction of intercellular adhesion molecule 1. We hypothesized that soluble Le y /H plays an important role in monocyte recruitment in RA. Methods We examined the role of H-2g in monocyte chemotaxis in vitro. We used an RA synovial tissue (ST)–SCID mouse chimera model to evaluate the role of H-2g in monocyte recruitment in vivo. We used Western blots to examine signaling molecules activated by H-2g in monocytes. Results H-2g induced human monocyte migration in vitro, which was mediated by Src and phosphatidylinositol 3-kinase (PI 3-kinase), since inhibitors and antisense oligodeoxynucleotides (ODNs) of Src and PI 3-kinase significantly decreased H-2g–induced monocyte migration ( P < 0.05). H-2g significantly increased mononuclear cell (MNC) homing in vivo into an RA ST–SCID mouse chimera ( P < 0.05). Transfection of MNCs with Src antisense ODNs blocked H-2g–induced MNC recruitment into the RA ST–SCID mouse chimera. Additionally, H-2g induced marked phosphorylation of protein kinase CΑI/ΒII (PKCΑI/ΒII), Src, IΚBΑ, and Akt in monocytes. Src, Akt, and NF-ΚB were shown to be downstream targets of PKCΑI/ΒII, since an inhibitor of PKCΑI/ΒII reduced H-2g–mediated phosphorylation of Src, Akt, and NF-ΚB in monocytes. Conclusion These data suggest that H-2g may be a novel mediator of monocyte recruitment in chronic inflammatory diseases like RA.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/58062/1/23296_ftp.pdf