Cyclic AMP Regulation of Neutrophil Apoptosis Occurs via a Novel Protein Kinase A-independent Signaling Pathway
| Autor: | Ian Dransfield, Adriano G. Rossi, Christopher Haslett, Morag C. Martin |
|---|---|
| Rok vydání: | 2001 |
| Předmět: |
Programmed cell death
Time Factors Transcription Genetic Cell Survival Neutrophils Blotting Western Apoptosis Inflammation Biology Biochemistry Enzyme activator Cyclic AMP medicine Humans Annexin A5 Cycloheximide Protein kinase A Molecular Biology Protein Synthesis Inhibitors Cell Death Kinase Cell Biology Cyclic AMP-Dependent Protein Kinases Adenosine Monophosphate Cell biology Enzyme Activation Bucladesine Microscopy Fluorescence Second messenger system medicine.symptom Signal transduction Granulocytes Protein Binding Signal Transduction |
| Zdroj: | Journal of Biological Chemistry. 276:45041-45050 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m105197200 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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