Dexamethasone modulates interleukin-12 production by inducing monocyte chemoattractant protein-1 in human dendritic cells.
Glucocorticoids have long been used as first-line immunosuppressants, although their precise mechanism of action has not been fully elucidated yet. This study evaluated the gene and protein expression of monocyte chemoattractant protein-1 (MCP-1), and its relationship with interleukin-12 and interleukin-10 synthesis, in human monocyte-derived dendritic cells exposed to dexamethasone. Dendritic cells were differentiated in the presence or in the absence of dexamethasone and then activated by IFN-gamma+soluble CD40 ligand; the gene and protein expression of target cytokines was measured by real-time PCR and ELISA, respectively. Our results showed that dexamethasone-primed mature dendritic cells expressed low levels of interleukin-12, and, at the opposite, high levels of interleukin-10 and MCP-1. Transfection experiments confirmed the ability of dexamethasone to activate MCP-1 gene promoter. Dexamethasone increased also MCP-2, but not MCP-3 synthesis, and the gene expression of CC chemokine receptor-2 by mature dendritic cells. The addition of anti-MCP-1 blocking antibody depressed MCP-1 release, and increased interleukin-12 production in dexamethasone-treated dendritic cells, thus demonstrating that interleukin-12 downregulation is largely dependent on MCP-1 overexpression. Our findings suggest that the induction of MCP expression in human dendritic cells by dexamethasone, and the amplification of cell response via the upregulation of the chemokine cognate receptor, may be critical to inhibit type 1 T-helper-biased immune response and, possibly, to favor type 2 T-helper-skewed response.
Roca
Leonarda
L
Division of Nephrology and Dialysis, Department of Biomedical Sciences and Bioagromed, University of Foggia, Foggia, Italy.
Di Paolo
Salvatore
S
Petruzzelli
Virna
V
Grandaliano
Giuseppe
G
Ranieri
Elena
E
Schena
Francesco Paolo
FP
Gesualdo
Loreto
L
D018932:Chemokine CCL2 / Q000235:genetics* / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects* / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D018664:Interleukin-12 / Q000096:biosynthesis*; D011401:Promoter Regions, Genetic / Q000235:genetics; D054390:Receptors, CCR2 / Q000235:genetics / Q000378:metabolism; D014162:Transfection
D018932:Chemokine CCL2; D054390:Receptors, CCR2; D018664:Interleukin-12; D003907:Dexamethasone