Cyclin-dependent kinase inhibitor drugs as potential novel anti-inflammatory and pro-resolution agents.
The cyclin-dependent kinase inhibitor (CDKi) drugs such as R-roscovitine have emerged as potential anti-inflammatory, pharmacological agents that can influence the resolution of inflammation. Usually, once an inciting inflammatory stimulus has been eliminated, resolution proceeds by prompt, safe removal of dominant inflammatory cells. This is accomplished by programmed cell death (apoptosis) of prominent effector, inflammatory cells typified by the neutrophil. Apoptosis of neutrophils ensures that toxic neutrophil granule contents are securely packaged in apoptotic bodies and expedites phagocytosis by professional phagocytes such as macrophages. A panel of CDKi drugs have been shown to promote neutrophil apoptosis in a concentration- and time-dependent manner and the archetypal CDKi drug, R-roscovitine, overrides the anti-apoptotic effects of powerful survival factors [including lipopolysaccharide (LPS) and granulocyte macrophage-colony stimulating factor (GM-CSF)]. Inflammatory cell longevity and survival signalling is integral to the inflammatory process and any putative anti-inflammatory agent must unravel a complex web of redundancy in order to be effective. CDKi drugs have also been demonstrated to have significant effects on other cell types including lymphocytes and fibroblasts indicating that they may have pleiotropic anti-inflammatory, pro-resolution activity. In keeping with this, CDKi drugs like R-roscovitine have been reported to be efficacious in resolving established animal models of neutrophil-dominant and lymphocyte-driven inflammation. However, the mechanism of action behind these powerful effects has not yet been fully elucidated. CDKs play an integral role in the regulation of the cell cycle but are also recognized as participants in processes such as apoptosis and transcriptional regulation. Neutrophils have functional CDKs, are transcriptionally active and demonstrate augmented apoptosis in response to CDKi drugs, while lymphocyte proliferation and secretory function are inhibited. This review will discuss current understanding of the processes of inflammation and resolution but will focus on CDKis and their potential mechanisms of action.
Leitch
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MRC Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh Medical School, 47 Little France Crescent, Edinburgh, UK.
Haslett
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Rossi
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AG
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy*; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D011687:Purines; D000077546:Roscovitine
D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D011687:Purines; D000077546:Roscovitine