Effects of PDE4 inhibitors on lipopolysaccharide-induced priming of superoxide anion production from human mononuclear cells

Aims: Phosphodiesterase 4 (PDE4) inhibitors have been described as potent a nti-inflammatory compounds, involving an increase in intracellular levels o f 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 wi th the cell permeable analogue of cyclic AMP, dibutyryl-cyclic AMP (db-cAMP ) and the anti-inflammatory cytokine interleukin-10 (IL-10) on superoxide a nion production from peripheral blood mononuclear cells preincubated with l ipopolysaccharide (LPS). Major findings: We report that, after incubation of the cells with LPS, a l arge increase in superoxide anion production was observed. Rolipram or RP 7 3-401 (10(-8) to 10(-5) M) induced significant reductions of flMLP-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 f MLP-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. Principal conclusion: 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.