Signaling events following chemokine receptor ligation in human dendritic cells at different developmental stages

Responsiveness of dendritic cells (DC) to inflammatory CC chemokines is dow n-regulated during their maturation. We analyzed the mechanism underlying t hese events. Cell-surface expression of CC chemokine receptor (CCR)-1, -3 a nd -5 was increased during differentiation of immature DC (IDC) from monocy tes, In contrast, these expressions were decreased during development of ID C into mature DC (mDC) to levels similar to those of monocytes, Transcripti onal expression of CCR-1, -3 and -5 was increased during differentiation of iDC from monocytes, while the expression was decreased during development of iDC into mDC, Expression of CCR-7 transcript was detected in mDC, but no t in monocytes or iDC, Both monocytes and iDC, but not mDC, migrated in res ponse to inflammatory CC chemokines such as regulated on activation normal T cell expressed and secreted (RANTES)/CCL5, whereas mDC, but not monocytes or IDC, migrated to macrophage inflammatory protein (MIP)-3 beta /CCL19. R eceptor engagement of monocytes or iDC by RANTES (for CCR-1, -3 and -5) res ulted in protein tyrosine phosphorylation events including activation of fo cal adhesion kinase as well as mitogen-activated protein kinase, whereas th is stimulation induced little activation of these molecular events in mDC w hen compared with monocytes or iDC. On the other hand, stimulation with MIP -3 beta (for CCR-7) induced tyrosine phosphorylation events in mDC, but not in monocytes or IDC, These results suggest that the down-regulation of cel l-surface expression of CCR and of their downstream signaling events may be involved in the reduced chemotaxis of DC to inflammatory CC chemokines dur ing their maturation.