CCR7-specific migration to CCL19 and CCL21 is induced by PGE2 stimulation in human monocytes: Involvement of EP2/EP4 receptors activation

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 E-2 (PGE(2)) regulates the expression and the activity of CCR7 in human blood-isolated monocytes as well as in the MONO-MAC-1 cell lineage. PGE(2) 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 PGE(2)-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 MAN was induced by PGE(2), we observed that PGE(2) can downregulate p42/p44 MAPK phosphorylation. At the transcription level, inhibition of p38 MAN inhibits CCR7 mRNA expression. Finally, we demonstrated that transcription factors CREB-1 and C/EBP alpha and C/EBP beta are translocated to the nucleus following PGE(2) 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. (C) 2008 Elsevier Ltd. All rights reserved.