Inhibition of eosinophil survival by a selective inhibitor of phosphodiesterase 4 via the induction of apoptosis.
Selective inhibitors of phosphodiesterases (PDEs) have been suggested to have anti-inflammatory effects on bronchial asthma through the inhibition of chemotaxis, adhesion, degranulation, the respiratory burst, and survival prolongation of eosinophils. However, the mechanisms by which these agents inhibit eosinophil survival remain unclear. We therefore investigated the possible mechanisms of inhibitory effects of selective inhibitors of PDE 3 (cilostazol) and PDE 4 (rolipram) on granulocyte-macrophage colony-stimulating factor (GM-CSF)-mediated eosinophil survival. Purified blood eosinophils were cultured with medium alone or GM-CSF (0.01 ng/ml) in the presence or absence of the agents for up to 6 d. DNA was extracted from freshly isolated eosinophils and eosinophils cultured for 2 d with medium alone, GM-CSF, or GM-CSF in the presence of the agents, and analyzed using agarose gel electrophoresis. The presence of rolipram (10(-4), 10(-5), 10(-6) M), but not cilostazol, significantly inhibited eosinophil survival at days 2, 4, and 6. A laddering pattern was observed in the DNA of eosinophils cultured with medium alone and with GM-CSF in the presence of rolipram. The results reveal that selective PDE 4 inhibitors inhibit GM-CSF-mediated eosinophil survival through the induction of apoptosis.
Wang
Way
W
Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Seiryo-machi, Sendai, Japan.
Masu
Kazuko
K
Tamura
Gen
G
Suzuki
Ko
K
Ohwada
Keiko
K
Okuyama
Kaori
K
Shirato
Kunio
K
Takayanagi
Motoaki
M
Ohno
Isao
I
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004305:Dose-Response Relationship, Drug; D004804:Eosinophils / Q000187:drug effects* / Q000201:enzymology*; D006801:Humans; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*
D010726:Phosphodiesterase Inhibitors; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4