| Autor: |
Leitch AE; MRC Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh Medical School, Edinburgh, Scotland, UK., Lucas CD, Marwick JA, Duffin R, Haslett C, Rossi AG |
| Jazyk: |
angličtina |
| Zdroj: |
Cell death and differentiation [Cell Death Differ] 2012 Dec; Vol. 19 (12), pp. 1950-61. Date of Electronic Publication: 2012 Jun 29. |
| DOI: |
10.1038/cdd.2012.80 |
| Abstrakt: |
Terminally differentiated neutrophils are short-lived but the key effector cells of the innate immune response, and have a prominent role in the pathogenesis and propagation of many inflammatory diseases. Delayed apoptosis, which is responsible for their extended longevity, is critically dependent on a balance of intracellular survival versus pro-apoptotic proteins. Here, we elucidate the mechanism by which the cyclin-dependent kinase (CDK) inhibitor drugs such as R-roscovitine and DRB (5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole) mediate neutrophil apoptosis. We demonstrate (by a combination of microarray, confocal microscopy, apoptosis assays and western blotting) that the phosphorylation of RNA polymerase II by CDKs 7 and 9 is inhibited by R-roscovitine and that specific effects on neutrophil transcriptional capacity are responsible for neutrophil apoptosis. Finally, we show that specific CDK7 and 9 inhibition with DRB drives resolution of neutrophil-dominant inflammation. Thus, we highlight a novel mechanism that controls both primary human neutrophil transcription and apoptosis that could be targeted by selective CDK inhibitor drugs to resolve established inflammation. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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