Agents that elevate cAMP inhibit human neutrophil apoptosis.
Neutrophil apoptosis, determined after 20 h in culture using standard criteria and shedding of cell surface CD16 (Fc gamma RIII), is dramatically inhibited, in a concentration-dependent manner, by the cAMP analogs, dibutyryl-cAMP and 8-Br-cAMP, and the adenylyl cyclase activator, forskolin. Furthermore, the stable receptor-directed PGD2 mimetic, ZK 118.182, and the PGE2 mimetic, 11-deoxy PGE1, similarly inhibited apoptosis. The DP-receptor antagonist BW A868C blocked the effect of ZK 118.182 and the protein kinase A inhibitor H-89 reversed the inhibition of apoptosis induced by dibutyryl-cAMP. These results clearly show that neutrophil apoptosis is markedly attenuated by cAMP elevating agents. This nucleotide second messenger may play a fundamental role in controlling neutrophil longevity and pharmacological regulation of cAMP levels or actions may influence neutrophil apoptosis in vivo.
Rossi
A G
AG
Department of Medicine, Rayne Laboratory, University of Edinburgh Medical School, UK.
Cousin
J M
JM
Dransfield
I
I
Lawson
M F
MF
Chilvers
E R
ER
Haslett
C
C
D000527:Alprostadil / Q000031:analogs & derivatives / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D015237:Dinoprost / Q000031:analogs & derivatives / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D009504:Neutrophils / Q000166:cytology* / Q000187:drug effects; D011459:Prostaglandins E, Synthetic / Q000494:pharmacology; D017452:Receptors, IgG / Q000378:metabolism; D013449:Sulfonamides
D004791:Enzyme Inhibitors; D007546:Isoquinolines; D011459:Prostaglandins E, Synthetic; D017452:Receptors, IgG; D013449:Sulfonamides; C067426:ZK 118182; D005576:Colforsin; D015237:Dinoprost; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D000527:Alprostadil; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; C034008:11-deoxyprostaglandin E1