Prostaglandin E(2) (PGE(2)) plays an important role in the immune response by modulating the complex interactions between leukocytes and tissue cells under inflammatory conditions. PGE(2) may possibly influence pro-inflammatory effects of chemokines and chemokine receptors that are among the main regulators of directional leukocyte migration. We analyzed whether PGE(2) affects chemokine receptor expression on human monocytes and their functional responsiveness to inflammatory chemokines. Expression of CCR5 on monocytes was significantly reduced, whereas CCR2 and CXCR4 expression were not affected by PGE(2). However, PGE(2 )treatment significantly increased the chemotactic response of monocytes to monocyte-chemoattractant protein-1 (MCP-1), RANTES and stromal cell-derived factor-1 (SDF-1). In addition, PGE(2) induced a higher calcium mobilization and actin polymerization upon chemokine stimulation. To better characterize PGE(2) effects, we used specific agonists for the PGE(2) receptors (EP(1) - EP(4)) characterized so far. The 11-deoxy PGE(1), an EP(2) /EP(4 )ligand, could mimic the effects observed using PGE(2). In contrast, the EP(1 )agonist, sulprostone, had not effects on monocytes, indicating that the effects of PGE(2) are mediated by EP(2)/EP(4 )receptors. Monocytes acquire a higher functional responsiveness to MCP-1, RANTES and SDF-1 after exposure to PGE(2), independently of the level of chemokine receptor expression. This mechanism might enhance the local monocyte recruitment under inflammatory conditions, and suggests specific PGE(2) receptor EP(2)/EP(4) antagonists as novel agents for the treatment of inflammatory diseases.