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

Cell Death Differ. 2012 Dec;19(12):1950-61. doi: 10.1038/cdd.2012.80. Epub 2012 Jun 29.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Cyclin-Dependent Kinase 9 / antagonists & inhibitors
  • Cyclin-Dependent Kinase 9 / metabolism*
  • Cyclin-Dependent Kinases / antagonists & inhibitors
  • Cyclin-Dependent Kinases / metabolism*
  • Dichlororibofuranosylbenzimidazole / pharmacology
  • HL-60 Cells
  • Hep G2 Cells
  • Humans
  • Inflammation / metabolism
  • Inflammation / pathology
  • Neutrophils / drug effects
  • Neutrophils / enzymology*
  • Phosphorylation
  • Protein Kinase Inhibitors / pharmacology*
  • Purines / pharmacology
  • RNA Polymerase II / metabolism
  • Roscovitine
  • Transcription, Genetic

Substances

  • Protein Kinase Inhibitors
  • Purines
  • Roscovitine
  • Dichlororibofuranosylbenzimidazole
  • Cyclin-Dependent Kinase 9
  • Cyclin-Dependent Kinases
  • cyclin-dependent kinase-activating kinase
  • RNA Polymerase II