Cyclin-dependent kinase inhibitors enhance the resolution of inflammation by promoting inflammatory cell apoptosis

Nat Med. 2006 Sep;12(9):1056-64. doi: 10.1038/nm1468. Epub 2006 Sep 3.


Apoptosis is essential for clearance of potentially injurious inflammatory cells and subsequent efficient resolution of inflammation. Here we report that human neutrophils contain functionally active cyclin-dependent kinases (CDKs), and that structurally diverse CDK inhibitors induce caspase-dependent apoptosis and override powerful anti-apoptosis signals from survival factors such as granulocyte-macrophage colony-stimulating factor (GM-CSF). We show that the CDK inhibitor R-roscovitine (Seliciclib or CYC202) markedly enhances resolution of established neutrophil-dependent inflammation in carrageenan-elicited acute pleurisy, bleomycin-induced lung injury, and passively induced arthritis in mice. In the pleurisy model, the caspase inhibitor zVAD-fmk prevents R-roscovitine-enhanced resolution of inflammation, indicating that this CDK inhibitor augments inflammatory cell apoptosis. We also provide evidence that R-roscovitine promotes apoptosis by reducing concentrations of the anti-apoptotic protein Mcl-1. Thus, CDK inhibitors enhance the resolution of established inflammation by promoting apoptosis of inflammatory cells, thereby demonstrating a hitherto unrecognized potential for the treatment of inflammatory disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Chloromethyl Ketones / pharmacology
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Azepines / pharmacology
  • Carrageenan
  • Caspase 3 / physiology
  • Cyclin-Dependent Kinases / antagonists & inhibitors*
  • Enzyme Inhibitors / therapeutic use*
  • Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology
  • Humans
  • Inflammation / drug therapy*
  • Male
  • Mice
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins / biosynthesis
  • Neutrophils / drug effects
  • Neutrophils / physiology*
  • Pleurisy / chemically induced
  • Pleurisy / drug therapy
  • Proto-Oncogene Proteins c-bcl-2 / biosynthesis
  • Purines / pharmacology
  • Pyrroles / pharmacology
  • Roscovitine


  • Amino Acid Chloromethyl Ketones
  • Azepines
  • Enzyme Inhibitors
  • Mcl1 protein, mouse
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Purines
  • Pyrroles
  • benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
  • Roscovitine
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Carrageenan
  • hymenialdisine
  • Cyclin-Dependent Kinases
  • Caspase 3