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.