Published online before print January 24, 2006
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* Etablissement Français du Sang Centre Atlantique, Tours, France;
Inserm U 618, Protéases et Vectorisation Pulmonaires,
** PPF Analyse des Systèmes Biologiques, Département des Microscopies,
JE 2448 Cellules Dendritiques et Greffes,
|| Inserm EMI-HU 0211, Nutrition, Croissance et Cancer, and
IFR 135 Imagerie Fonctionnelle, Faculté de Médecine, Université de Tours, France; and
¶ Service d’Oncologie Médicale et Maladies du sang, Centre Hospitalier Régional et Universitaire, Tours, France
1Correspondence: Etablissement Français du Sang Centre Atlantique, Service Recherche, 2 boulevard Tonnellé, 37020 Tours Cedex, France. E-mail: valerie.chabot{at}efs.sante.fr
The proinflammatory chemokine CC chemokine ligand 5 (CCL5) is a potent chemoattractant of immature dendritic cells (iDCs). It remains to be elucidated whether CCL5 may also enhance iDC migration through the basement membrane by affecting matrix metalloproteinase (MMP)-9 secretion. In this study, iDCs were differentiated in vitro from human monocytes of healthy donors. Zymographic analysis of cellular membranes of nontreated iDCs revealed a basal secretion of the pro- and active MMP-9, whereas only pro-MMP-9 was detected in conditioned media. Increasing concentrations of CCL5 significantly enhanced MMP-9 secretion by iDCs, peaking at 100 ng/ml, which optimally increased iDC migration through a reconstituted basement membrane (MatrigelTM) in vitro. The CCL5-enhanced secretion of MMP-9 occurred early (2 h) and was maintained at least for 10 h. A significant increase in MMP-9 mRNA synthesis was detected by reverse transcriptase-polymerase chain reaction, only at 6 h of CCL5 treatment, which suggests that the early effect of CCL5 (0–4 h) on MMP-9 secretion was independent of mRNA synthesis, whereas the more delayed effect (6–10 h) could be mediated through an increase in MMP-9 gene expression. In a Matrigel migration assay, the CCL5-enhanced iDC migration was reduced significantly by specific inhibitors of MMP-9, such as tissue inhibitor of metalloproteinase-1 or an anti-MMP-9 antibody, which indicates that iDC migration through the basement membrane depends on MMP-9. These results suggest that under inflammatory conditions, the chemokine CCL5 may enhance iDC migration through the basement membrane by rapidly increasing their MMP-9 secretion.
Key Words: antigen-presenting cell • RANTES • gelatinase B • cellular membranes • cell trafficking
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