Differential effects of immunosuppressive drugs on chemokine receptor CCR7 in human monocyte-derived dendritic cells: selective upregulation by rapamycin.
BACKGROUND
Appropriate recruitment of dendritic cells (DC) at sites of inflammation and migration to secondary lymphoid organs is of critical importance for the initiation of Ag-specific immune responses. The proper localization of DC in selected tissues is guided primarily by the coordinated expression of chemokine receptors (CKR). Here we show that immunosuppressive drugs have divergent effects on the modulation of CKR in maturing DC.


RESULTS
Dexamethazone (DEX) and IL-10 inhibited human DC migration to CCL19 in vitro and mouse DC migration to lymph nodes (LN) in vivo, by impairing CCR7 expression. The calcineurin inhibitors cyclosporine A (CsA) and tacrolimus (FK506) were characterized by the inability to modulate CKR expression and migratory activity. Rapamycin (RAPA) increased DC migration to CCL19 in vitro and to LN in vivo by enhancing CCR7 expression. This effect could be mediated, in LPS-maturing DC, by the inhibition of autocrine IL-10 production. The in vivo data obtained with ex vivo RAPA treated DC were confirmed in a model of in vivo drug administration in mice, suggesting a potential clinical relevance.


CONCLUSIONS
These findings demonstrate that immunosuppressive agents differently modulate the CKR switch associated with maturing DC; in particular, RAPA selectively up-regulates CCR7 and enhances the migration of differentiated DC to regional LN. This study contributes to a better understanding of the role of immunosuppressive therapy on DC migration, a potentially relevant check point of immunosuppressive treatment.
Sordi
Valeria
V
Immunology of Diabetes Unit, San Raffaele Scientific Institute, Milan, Italy. sordi.valeria@hsr.it
Bianchi
Giancarlo
G
Buracchi
Chiara
C
Mercalli
Alessia
A
Marchesi
Federica
F
D'Amico
Giovanna
G
Yang
Cui-Hong
CH
Luini
Walter
W
Vecchi
Annunciata
A
Mantovani
Alberto
A
Allavena
Paola
P
Piemonti
Lorenzo
L
D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D002634:Chemotaxis, Leukocyte; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000502:physiology; D005786:Gene Expression Regulation; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008198:Lymph Nodes / Q000276:immunology; D051379:Mice; D023421:Models, Animal; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000235:genetics*; D020123:Sirolimus / Q000494:pharmacology*
C515370:CCR7 protein, human; C515371:Ccr7 protein, mouse; D007166:Immunosuppressive Agents; D054400:Receptors, CCR7; D019707:Receptors, Chemokine; D020123:Sirolimus