title: Cyclin-dependent kinases 7 and 9 specifically regulate neutrophil transcription and their inhibition drives apoptosis to promote resolution of inflammation.
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.
authors: MRC Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh Medical School, Edinburgh, Scotland, UK.
authors: A E
authors: AE
authors: Leitch
authors: C D
authors: CD
authors: Lucas
authors: J A
authors: JA
authors: Marwick
authors: R
authors: R
authors: Duffin
authors: C
authors: C
authors: Haslett
authors: A G
authors: AG
authors: Rossi
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D042863:Cyclin-Dependent Kinase 9 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004004:Dichlororibofuranosylbenzimidazole / Q000494:pharmacology; D018922:HL-60 Cells; D056945:Hep G2 Cells; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011687:Purines / Q000494:pharmacology; D012319:RNA Polymerase II / Q000378:metabolism; D000077546:Roscovitine; D014158:Transcription, Genetic; D000095043:Cyclin-Dependent Kinase-Activating Kinase
chemical_list: D047428:Protein Kinase Inhibitors; D011687:Purines; D000077546:Roscovitine; D004004:Dichlororibofuranosylbenzimidazole; D042863:Cyclin-Dependent Kinase 9; D018844:Cyclin-Dependent Kinases; D012319:RNA Polymerase II; D000095043:Cyclin-Dependent Kinase-Activating Kinase; C000722416:CDK7 protein, human