The immunomodulator FTY720 interferes with effector functions of human monocyte-derived dendritic cells.
The potent immunomodulator FTY720 elicits immunosuppression via acting on sphingosine 1-phosphate receptors (S1PR), thereby leading to an entrapment of lymphocytes in the secondary lymphoid tissue. To elucidate the potential in vitro effects of this drug on human monocyte-derived DC, we used low nanomolar therapeutic concentrations of FTY720 and phosphorylated FTY720 (FTY720-P) and investigated their influence on DC surface marker expression, protein levels of S1PR and DC effector functions: antigen uptake, chemotaxis, cytokine production, allostimulatory and Th-priming capacity. We report that both FTY720 and FTY720-P reduce chemotaxis of immature and mature DC. Mature DC generated in the presence of FTY720 or FTY720-P showed an impaired immunostimmulatory capacity and reduced IL-12 but increased IL-10 production. T cells cultured in the presence of FTY720- or FTY720-P-treated DC showed an altered cytokine production profile indicating a shift from Th1 toward Th2 differentiation. In treated immature and mature DC, expression levels for two S1PR proteins, S1P1 and S1P4, were reduced. We conclude that in vitro treatment with FTY720 affects DC features that are essential for serving their role as antigen-presenting cells. This might represent a new aspect of the overall immunosuppressive action of FTY720 and makes DC potential targets of further sphingolipid-derived drugs.
Müller
Hansgeorg
H
Department of Nephrology, Innsbruck Medical School, Innsbruck, Austria.
Hofer
Susanne
S
Kaneider
Nicole
N
Neuwirt
Hannes
H
Mosheimer
Birgit
B
Mayer
Gert
G
Konwalinka
Günther
G
Heufler
Christine
C
Tiefenthaler
Martin
M
D000199:Actins / Q000378:metabolism; D018821:CD18 Antigens / Q000235:genetics / Q000276:immunology*; D019013:CD40 Antigens / Q000276:immunology; D018925:Chemokines / Q000378:metabolism; D002633:Chemotaxis / Q000502:physiology; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D000068876:Fingolimod Hydrochloride; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D011409:Propylene Glycols / Q000494:pharmacology*; D013110:Sphingosine / Q000031:analogs & derivatives; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors
D000199:Actins; D018821:CD18 Antigens; D019013:CD40 Antigens; D018925:Chemokines; D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine