Several reports have identified monocyte chemoattractant protein (MCP)-1 as an essential chemokine involved in monocyte traffic across endo- and epithelial barriers both in vitro and in vivo. However, the contribution of endothelial MCP-1 signaling via the CCR2 receptor, in monocyte adhesion to inflamed endothelium under flow is incompletely understood. A sensitive flow chamber assay was used to assess monocyte adhesion to TNF-activated primary human pulmonary artery endothelial cells (HPAEC) during physiologic shear stress. Monocyte adhesion was markedly reduced (~45%) when endothelium-derived MCP-1 was either neutralized by pretreatment of HPAEC with anti-MCP-1 mAb, or when endothelial MCP-1 synthesis was inhibited by translational arrest of MCP-1 mRNA transcripts with phosphorothioate MCP-1 antisense oligomers. Corresponding efficacy was observed for blockade of monocyte CCR2 receptor function by anti-CCR2 mAb or MCP-1 antagonists (9-76 analogue). In contrast to HPAEC, the MCP-1-CCR2 axis exerted only minor impact on monocyte adhesion to HUVEC. Using selective blockade of either ß1 (VLA-4) or ß2 (LFA-1,Mac-1) integrin dependent monocyte adhesion, the impact of EC-derived MCP-1 on monocyte-HPAEC adhesion was shown to occur largely via the ß2 integrin adhesion pathway, but not via ß1 integrin. Compatible with these findings, pretreatment of monocytes with MCP-1 but not RANTES provoked a rapid and transient activationdependent neoepitope 24 expression on ß2 integrin -chains, as analyzed by increased reporter mAb24 binding. Collectively, our data demonstrate an important cross talk of endothelial MCP-1 with monocyte CCR2 effecting monocyte firm adhesion to inflamed HPAEC under physiologic flow conditions. Upregulation of monocyte ß2 integrin activity in response to MCP-1 is suggested as the underlying mechanism.