The defence mechanisms that enable our immune cells to battle pathogens are potentially deleterious to normal tissues, and so it is crucial that inflammation is resolved rapidly when no longer required. Reporting in Nature Medicine, Rossi and colleagues now show that cyclin-dependent kinase (CDK) inhibitors can be used to enhance the resolution of inflammation by inducing neutrophil apoptosis, which might represent a novel therapeutic strategy for inflammatory disorders.
Neutrophils are leukocytes with a central role in innate immunity — they are rapidly recruited to sites of infection and injury, secrete pro-inflammatory mediators and undergo apoptosis during the spontaneous resolution of inflammation. Perturbations to this process can result in autoimmune and chronic inflammatory disorders, and so the mechanisms involved in neutrophil apoptosis are attracting considerable interest.
Intriguingly, Rossi et al. found that small-molecule CDK inhibitors such as R-roscovitine (seliciclib or CYC202) are effective in inducing neutrophil apoptosis, and can even override the effect of powerful pro-survival factors such as lipopolysaccharide or granulocyte–macrophage colony-stimulating factor. This finding was surprising, as neutrophils are terminally differentiated, and it was traditionally thought that CDKs only control the fate of rapidly proliferating cells; indeed, several CDK inhibitors are currently in trials for the treatment of a number of cancer types.
To assess the therapeutic significance of their novel finding, the authors tested R-roscovitine in models of pleural inflammation, as well as bleomycin-induced lung injury and arthritis. Injection of R-roscovitine at the height of inflammation led to reduced release of pro-inflammatory mediators and enhanced resolution of inflammation, and also reduced bleomycin-induced lethality. Induction of apoptosis with CDK inhibitors was caspase dependent, and the authors also found that R-roscovitine seems to promote apoptosis by reducing concentrations of the anti-apoptotic protein MCL1.
As CDK inhibitors such as R-roscovitine have already demonstrated good tolerability in clinical trials, the specific induction of inflammatory cell apoptosis by CDK inhibitors might represent a powerful new approach for the treatment of diseases associated with increased or persistent inflammatory responses.
ORIGINAL RESEARCH PAPER
Rossi, A. G. et al. Cyclin-dependent kinase inhibitors enhance the resolution of inflammation by promoting inflammatory cell apoptosis. Nature Med. 12, 1056–1064 (2006)
Gilroy, D. W. et al. Inflammatory resolution: new opportunities for drug discovery. Nature Rev. Drug Discov. 3, 401–416 (2004)