Cyclin-dependent kinase inhibitors enhance the resolution of inflammation by promoting inflammatory
Author: ["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"]
Publication: Nature Medicine
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Abstract
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. NOTE: In the version of this article initially published, the dose stated for zVAD-fmk administration was incorrect. The methods reported on page 1062 should read “Twenty-four hours after intrapleural injection of carrageenan, mice were injected i.p. with 10 mg per kg of R-roscovitine and/or 5 mg per kg of zVAD-fmk (z-Val-Ala-DL-Asp-fluoromethylketone; Bachem)”. Similarly, the legend to figure 4, line 3, should read "C57/bl6 mice were treated with 10 mg per kg of R-roscovitine (i.p.) and/or 5 mg per kg of zVAD-fmk (i.p. at 4-h intervals)”. We also made an error reporting the time of administration of K/Bxn serum in the legend to figure 5, line 14. This should read “Mice (n =10 in each group) were injected twice (days 0 and 2) with K/BxN serum derived from arthritic (day 60) K/BxN transgenic mice." The error has been corrected in the HTML and PDF versions of the article.
Cite this article
Rossi, A., Sawatzky, D., Walker, A. et al. Cyclin-dependent kinase inhibitors enhance the resolution of inflammation by promoting inflammatory cell apoptosis. Nat Med 12, 1056–1064 (2006). https://doi.org/10.1038/nm1468
