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

Adriano G Rossi, Deborah A Sawatzky, Annemieke Walker, Carol Ward, Tara A Sheldrake, Nicola A Riley, Alison Caldicott, Magdalena Martinez-Losa, Trevor R Walker, Rodger Duffin, Mohini Gray, Elvira Crescenzi, Morag C Martin, Hugh J Brady, John S Savill, Ian Dransfield, Christopher Haslett

Research output: Contribution to journalArticlepeer-review


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.
Original languageEnglish
Pages (from-to)1056-64
Number of pages9
JournalNature Medicine
Issue number9
Publication statusPublished - 2006


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