Characterization of the phosphodiesterase (PDE) pattern of in vitro-generated human dendritic cells (DC) and the influence of PDE inhibitors on DC function.
During differentiation of human monocytes (CD14(+)/CD1a(-)) to CD14(-)/CD1a(+)dendritic cells (DC), a drastic decrease in PDE4 activity was observed, while activities of PDE1 and PDE3 substantially increased. DC released tumour necrosis factor-alpha (TNF) in response to lipopolysaccharide (LPS) challenge, which was abolished both by dexamethasone and the cyclic AMP-elevating drugs db-cAMP and PGE(2). In addition, rolipram, at PDE4-selective concentrations, blocked TNF release by 37 +/- 5% (P<0.05 vs. control). The PDE3 inhibitor motapizone only marginally influenced TNF synthesis, but a synergistic inhibitory effect was noted in combination with rolipram. Qualitatively, similar inhibitory effects were observed in DC-stimulated T cell responses. Motapizone, lacking efficacy when used alone, increased the effect of rolipram in blocking CD4(+)T lymphocyte proliferation in response to antigen (Ag) (tetanus toxoid, TT; keyhole limpet hemocyanin, KLH) presented by DC and in allogeneic mixed leukocyte reactions (MLR). However, in these coculture systems the T cells rather than the DC seem to be the major target cells of PDE-inhibitor action. In summary, PDE inhibitors can affect DC function directly as demonstrated by blocking TNF release and their efficacy reflects the changes in the PDE activity profile during differentiation from their monocyte precursors. These results together with the known efficacy of PDE3/4 inhibitors in T cells support the concept of combined PDE3/4 inhibitors for asthma therapy.
Gantner
F
F
Byk Gulden, Department of Biochemistry, University of Konstanz, Konstanz, Germany.
Schudt
C
C
Wendel
A
A
Hatzelmann
A
A
D002455:Cell Division / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D003712:Dendrites / Q000187:drug effects / Q000201:enzymology*; D005434:Flow Cytometry; D006433:Hemocyanins / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D018950:Lipopolysaccharide Receptors; D007959:Lymphocyte Culture Test, Mixed; D008264:Macrophages / Q000378:metabolism; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D013601:T-Lymphocytes / Q000187:drug effects; D013745:Tetanus Toxoid / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D016207:Cytokines; D018950:Lipopolysaccharide Receptors; D010726:Phosphodiesterase Inhibitors; D013745:Tetanus Toxoid; D014409:Tumor Necrosis Factor-alpha; D006433:Hemocyanins; D010727:Phosphoric Diester Hydrolases; C032808:keyhole-limpet hemocyanin