Cyclic AMP regulation of neutrophil apoptosis occurs via a novel protein kinase A-independent signaling pathway.
The second messenger molecule cyclic AMP dramatically modulates the apoptotic program in a wide variety of cells, accelerating apoptosis in some and delaying the rate of apoptosis in others. Human neutrophil apoptosis, a process that regulates the fate and numbers of these potentially histotoxic cells in inflammatory sites, is profoundly delayed by the cell-permeable analog of cyclic AMP, dibutyryl-cAMP. We have investigated the mechanisms underlying cyclic AMP-mediated delay of neutrophil apoptosis, and we show that cyclic AMP inhibits loss of mitochondrial potential occurring during constitutive neutrophil apoptosis. Furthermore, we demonstrate that cyclic AMP also suppresses caspase activation in these inflammatory cells. Despite increasing protein kinase A activity, this kinase is unlikely to mediate the effect of cyclic AMP on apoptosis because blockade of protein kinase A activation did not influence the survival effects of cyclic AMP. Further investigation of the signaling mechanism demonstrated that the delay of apoptosis is independent of phosphoinositide 3-kinase and MAPK activation. Our results suggest cyclic AMP delays neutrophil apoptosis via a novel, reversible, and transcriptionally independent mechanism. We show that proteasome activity in the neutrophil is vitally involved in this process, and we suggest that a balance of pro-apoptotic and anti-apoptotic proteins plays a key role in the powerful ability of cyclic AMP to delay neutrophil death.
Martin
M C
MC
Medical Research Council Centre for Inflammation Research, Respiratory Medicine Unit, University of Edinburgh Medical School, Edinburgh EH8 9AG, United Kingdom. moragmarton@hotmail.com
Dransfield
I
I
Haslett
C
C
Rossi
A G
AG
D000249:Adenosine Monophosphate / Q000378:metabolism; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis; D015153:Blotting, Western; D003994:Bucladesine / Q000378:metabolism; D016923:Cell Death; D002470:Cell Survival; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D003513:Cycloheximide / Q000494:pharmacology; D004789:Enzyme Activation; D006098:Granulocytes / Q000378:metabolism; D006801:Humans; D007249:Inflammation; D008856:Microscopy, Fluorescence; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology*; D011485:Protein Binding; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D015398:Signal Transduction; D013997:Time Factors; D014158:Transcription, Genetic
D017304:Annexin A5; D011500:Protein Synthesis Inhibitors; D000249:Adenosine Monophosphate; D003994:Bucladesine; D003513:Cycloheximide; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases