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

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Original languageEnglish
Pages (from-to)1950-1961
Number of pages12
JournalCell Death and Differentiation
Volume19
Issue number12
DOIs
Publication statusPublished - Dec 2012

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.Cell Death and Differentiation advance online publication, 29 June 2012; doi:10.1038/cdd.2012.80.

    Research areas

  • CELL-DEATH, inflammation, DOWN-REGULATION, apoptosis, LIPOPOLYSACCHARIDE, resolution, AGING NEUTROPHILS, P-TEFB, MCL-1, MACROPHAGES, IN-VITRO, INTERFERON-GAMMA, neutrophil, cyclin-dependent kinase, RNA-POLYMERASE-II

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