Effects of PDE4 inhibitors on lipopolysaccharide-induced priming of superoxide anion production from human mononuclear cells.
OBJECTIVE
Phosphodiesterase 4 (PDE4) inhibitors have been described as potent anti-inflammatory compounds, involving an increase in intracellular levels of cyclic 3',5'-adenosine monophosphate (AMP). The aim of this study was to compare the effects of selective PDE4 inhibitors, rolipram and RP 73-401 with the cell permeable analogue of cyclic AMP, dibutyryl-cyclic AMP (db-cAMP) and the anti-inflammatory cytokine interleukin-10 (IL-10) on superoxide anion production from peripheral blood mononuclear cells preincubated with lipopolysaccharide (LPS).


RESULTS
We report that, after incubation of the cells with LPS, a large increase in superoxide anion production was observed. Rolipram or RP 73-401 (10(-8) to 10(-5) M) induced significant reductions of fMLP-induced superoxide anion production in cells incubated with or without LPS. The db-cAMP (10(-5) to 10(-3) M) also elicited dose-dependent inhibitions of the fMLP-induced superoxide anion production. In contrast, IL-10 (1 or 10 ng/ml) did not elicit a reduction in fMLP-induced superoxide anion production in both conditions.


CONCLUSIONS
These results suggest that the inhibitory activity of PDE4 inhibitors on fMLP-induced production of superoxide anion production is mediated by db-cAMP rather than IL-10.
Germain
N
N
INSERM U456, Laboratoire de Pharmacodynamie et de Pharmacologie Moléculaire, Faculté des Sciences, Pharmaceutiques et Biologiques, Université de Rennes 1, France.
Corbel
M
M
Belleguic
C
C
Boichot
E
E
Lagente
V
V
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism*; D001549:Benzamides / Q000494:pharmacology*; D003994:Bucladesine / Q000494:pharmacology; D002478:Cells, Cultured; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D006801:Humans; D016753:Interleukin-10 / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D020889:Rolipram / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism*; D013997:Time Factors
D001549:Benzamides; D008070:Lipopolysaccharides; D010726:Phosphodiesterase Inhibitors; D011725:Pyridines; D013481:Superoxides; D016753:Interleukin-10; D009240:N-Formylmethionine Leucyl-Phenylalanine; D003994:Bucladesine; C042932:formylmethionyl-leucyl-phenylalanine methyl ester; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram; C087566:piclamilast