title: Inhibition of cGMP-dependent protein kinases potently decreases neutrophil spontaneous apoptosis.
abstract: The signalling pathways mediating neutrophil spontaneous apoptosis are still largely unknown. We report that the indolocarbazole compound KT5823, a specific inhibitor of cGMP-dependent protein kinases (cGK), dose-dependently inhibited spontaneous apoptosis of neutrophils. At the concentration eliciting the maximum effect (8 microM), it decreased apoptosis from 72.42+/-12.79% to 45.86+/-7.22% (p=0.0002, n=6). Similarly, the isoquinoline sulfonamide compound H89, another cGK inhibitor, prevented neutrophil apoptosis. At the concentration eliciting the maximum effect (20 microM), it decreased apoptosis from 72.42+/-12.79% to 31.84+/-10.70% (p=0.0004, n=6). The maximum effect of KT5823 and H89 was comparable to that of GM-CSF and LPS, respectively. Moreover, YC-1, a soluble guanylate cyclase activator, and 4-([3',4',-(methylenedioxy)benzyl]amino)-6-methoxyquinazoline, a specific phosphodiesterase 5 inhibitor, enhanced neutrophil apoptosis, and their effect was antagonised by KT5823. Taken together, these observations highlight a new role of cGK as important mediators of neutrophil spontaneous apoptosis.
authors.affiliation: Laboratory of Immunopathology, Istituto di Ricerche Farmacologiche Mario Negri, Consorzio Mario Negri Sud, Via Nazionale, 66030 S. Maria Imbaro (Chieti), Italy. brunetti@negrisud.it
authors.forename: Mauro
authors.initials: M
authors.lastname: Brunetti
authors.forename: Nicola
authors.initials: N
authors.lastname: Mascetra
authors.forename: Stefano
authors.initials: S
authors.lastname: Manarini
authors.forename: Nicola
authors.initials: N
authors.lastname: Martelli
authors.forename: Chiara
authors.initials: C
authors.lastname: Cerletti
authors.forename: Piero
authors.initials: P
authors.lastname: Musiani
authors.forename: Francesca B
authors.initials: FB
authors.lastname: Aiello
authors.forename: Virgilio
authors.initials: V
authors.lastname: Evangelista
mesh_terms: D000470:Alkaloids / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002227:Carbazoles; D002478:Cells, Cultured; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007211:Indoles; D007546:Isoquinolines / Q000494:pharmacology; D007700:Kinetics; D009504:Neutrophils / Q000166:cytology / Q000201:enzymology / Q000502:physiology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D013449:Sulfonamides
chemical_list: D000470:Alkaloids; D002227:Carbazoles; D004791:Enzyme Inhibitors; D007211:Indoles; D007546:Isoquinolines; D010726:Phosphodiesterase Inhibitors; D013449:Sulfonamides; C073601:KT 5823; D017869:Cyclic GMP-Dependent Protein Kinases; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide