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.
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Change history
10 November 2006
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.
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Acknowledgements
We thank M. Clay and K. Miles for help with the in vivo models. We thank the Arthritis Research Campaign, the Medical Research Council, UK, the Norman Salvesen Emphysema Trust, Asthma UK, and the Juan Esplugues Foundation for financial support.
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A.G.R. initiated, designed, directed and performed experiments and took overall responsibility for planning and writing the manuscript. D.A.S. helped design, perform and analyze the in vivo experiments and contributed to the writing of the in vivo component. A.W. helped design, perform and analyze the in vitro experiments and contributed to the writing of the in vitro component. C.W. contributed intellectually to the manuscript and helped with the in vitro work. T.A.S. performed some in vitro apoptosis and western blotting experiments. N.A.R. performed the Mcl-1 western blot experiments. A.C. and M.M.-L. performed some in vitro apoptosis experiments. T.R.W. helped in the design of the western blotting and kinase experiments. R.D. helped in the bleomycin experiments. M.G. helped in the design and execution of the arthritis experiments. E.C. helped in the design and execution of the kinase experiments. M.C.M. performed preliminary apoptosis experiments with the CDK inhibitors. H.J.B. provided intellectual input and provided significant input to the design and execution of the kinase experiments. J.S.S. provided intellectual input. I.D. provided intellectual input and contributed to the design of the experiments and the writing of the manuscript. C.H. provided intellectual input and helped in the design and coordination of the project.
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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
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DOI: https://doi.org/10.1038/nm1468
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