The recent demonstration that newly recruited monocytes do not die at the site of inflammation, but migrate to draining lymph nodes, raises the question on the mechanism involved in this process. In this study, we demonstrate for the first time that prostaglandin E₂ (PGE₂) regulates the expression and the activity of CCR7 in human blood-isolated monocytes as well as in the MONO-MAC-1 cell lineage. PGE₂ induces intracellular cAMP formation through engagement of the E-prostanoid 2/E-prostanoid 4 (EP₂/EP₄) receptors present on monocytes. Migration to chemokines CCL19 and CCL21 in the PGE₂-stimulated monocytes is mediated through the augmentation of cAMP concentration and furthermore, the cAMP/PKA pathway appears to act as the major inducer of CCR7 transcription in MONO-MAC-1. While p38 MAPK was induced by PGE₂, we observed that PGE₂ can downregulate p42/p44 MAPK phosphorylation. At the transcription level, inhibition of p38 MAPK inhibits CCR7 mRNA expression. Finally, we demonstrated that transcription factors CREB-1 and C/EBPα and C/EBPβ are translocated to the nucleus following PGE₂ stimulation and bind the potent CCR7 promoter region. Our findings may have important implication for HIV-1 migration to the lymph nodes since macrophages and monocytes, particularly CD16 positive subset, are susceptible to HIV-1 infection.