Effects of selective phosphodiesterase type IV inhibitor, rolipram, on signal transducing phospholipases in neutrophil: inhibition of phospholipases A2, D but not C.
The effects of a selective phosphodiesterase (PDE) type IV inhibitor, rolipram, on activation of neutrophil phospholipases in response to the chemotactic peptide formyl-methiony-leucyl-phenylalanine (fMLP) were investigated. fMLP caused liberation of arachidonic acid, a precursor of eicosanoids and in the presence of 0.3% butanol, production of phosphatidylbutanol, an indicator of phospholipase D activation. Rolipram inhibited arachidonic acid release and phosphatidylbutanol formation. The inhibition was considered to be mediated through a cAMP-dependent mechanism, probably protein kinase A, because selective inhibitors for protein kinase A, H-8 or H-89 overcame the action of rolipram. The concentration-dependent inhibitory profile for phospholipase D activation was similar to that for lysosomal enzyme release, providing additional evidence for the functional link of these two events. In contrast, rolipram was without effect on fMLP-induced inositol trisphosphate production. These results indicate that this selective PDE IV inhibitor had no effect on phosphatidylinositol-specific phospholipase C activation but effectively prevented activation of phospholipases A2 and D coupled to arachidonic acid liberation and lysosomal enzyme release, respectively.
Nakashima
S
S
Department of Biochemistry, Gifu University School of Medicine, Japan.
Mizutani
T
T
Nakamura
Y
Y
Takemura
S O
SO
Nakamura
M
M
Miyata
H
H
Katagiri
Y
Y
Nozawa
Y
Y
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000378:metabolism; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010739:Phospholipase D / Q000037:antagonists & inhibitors; D010740:Phospholipases / Q000037:antagonists & inhibitors*; D010741:Phospholipases A / Q000037:antagonists & inhibitors; D047428:Protein Kinase Inhibitors; D011760:Pyrrolidinones / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D020889:Rolipram; D015398:Signal Transduction / Q000187:drug effects*; D013449:Sulfonamides; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors
D004791:Enzyme Inhibitors; D007295:Inositol Phosphates; D007546:Isoquinolines; D010726:Phosphodiesterase Inhibitors; D047428:Protein Kinase Inhibitors; D011760:Pyrrolidinones; D013449:Sulfonamides; D016718:Arachidonic Acid; D009240:N-Formylmethionine Leucyl-Phenylalanine; D010740:Phospholipases; D010741:Phospholipases A; D010738:Type C Phospholipases; D010739:Phospholipase D; D020889:Rolipram; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide