Cyclin-dependent kinases 7 and 9 specifically regulate neutrophil transcription and their inhibition drives apoptosis to promote resolution of inflammation
Language: 
English
Abstract: 

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.

Author(s): 
Leitch, A. E.
Lucas, C. D.
Marwick, J. A.
Duffin, R.
Haslett, C.
Rossi, A. G.
Item Type: 
Journal Article
Publication Title: 
Cell Death and Differentiation
Journal Abbreviation: 
Cell Death Differ.
Publication Date: 
2012-12
Publication Year: 
2012
Pages: 
1950-1961
Volume: 
19
Issue: 
12
ISSN: 
1476-5403
DOI: 
10.1038/cdd.2012.80
Library Catalog: 
NCBI Published Medical (?)
Extra: 
PMID: 22743999 PMCID: PMC3504709

Turabian/Chicago Citation

A. E. Leitch, C. D. Lucas, J. A. Marwick, R. Duffin, C. Haslett and A. G. Rossi. 2012-12. "Cyclin-dependent kinases 7 and 9 specifically regulate neutrophil transcription and their inhibition drives apoptosis to promote resolution of inflammation." Cell Death and Differentiation 19: 12: 1950-1961. 10.1038/cdd.2012.80.

Wikipedia Citation

<ref> {{Cite journal | doi = 10.1038/cdd.2012.80 | issn = 1476-5403 | volume = 19 | pages = 1950-1961 | last = Leitch | first = A. E. | coauthors = Lucas, C. D., Marwick, J. A., Duffin, R., Haslett, C., Rossi, A. G. | title = Cyclin-dependent kinases 7 and 9 specifically regulate neutrophil transcription and their inhibition drives apoptosis to promote resolution of inflammation | journal = Cell Death and Differentiation | date = 2012-12 | pmid = | pmc = }} </ref>