Cyclic AMP delays neutrophil apoptosis via stabilization of Mcl-1☆

Abstract 

Human neutrophils underwent spontaneous apoptosis, which was accompanied by degradation of Mcl-1, but not other anti-apoptotic molecules (cIAP1, cIAP2, A1, survivin and Bcl-2). Spontaneous neutrophil apoptosis and Mcl-1 degradation were prevented by cyclic AMP (cAMP) agonists (dibutyryl cAMP and prostaglandin E₁), and the effects of cAMP agonists on neutrophils were highly resistant to cycloheximide, a protein synthesis inhibitor, although slight increase in Mcl-1 mRNA expression was induced by cAMP agonists. Proteasome inhibitors (epoxomicin and lactacystin) also prevented spontaneous neutrophil apoptosis and Mcl-1 degradation to the same extent as cAMP agonists, and no additive effect was obtained by combination of cAMP agonists and proteasome inhibitors. These findings suggest that cAMP agonists, like proteasome inhibitors, delay neutrophil apoptosis primarily via stabilization of Mcl-1.

Abbreviations: cAMP, cyclic AMP, ECL, enhanced chemiluminescence, ERK, extracellular signal-regulated kinase, G-CSF, granulocyte colony-stimulating factor, GM-CSF, granulocyte-macrophage CSF, IAP, inhibitor of apoptosis, PCR, polymerase chain reaction, PGE₁, prostaglandin E₁, PI, propidium iodide, PI3K, phosphatidylinositol 3-kinase, PKA, cAMP-dependent protein kinase

Keywords: Mcl-1, Apoptosis, Cyclic AMP, Proteasome, Neutrophils