The CDK inhibitor, R-roscovitine, promotes eosinophil apoptosis by down-regulation of Mcl-1

Eosinophils are major players in inflammatory allergic diseases such as asthma, hay fever and eczema. Here we show that the cyclin-dependent kinase inhibitor (CDKi) R-roscovitine efficiently and rapidly induces human eosinophil apoptosis using flow cytometric analysis of annexin-V/propidium iodide s...

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Published inFEBS letters Vol. 583; no. 15; pp. 2540 - 2546
Main Authors Duffin, Rodger, Leitch, Andrew E., Sheldrake, Tara A., Hallett, John M., Meyer, Colette, Fox, Sarah, Alessandri, Ana L., Martin, Morag C., Brady, Hugh J., Teixeira, Mauro M., Dransfield, Ian, Haslett, Christopher, Rossi, Adriano G.
Format Journal Article
LanguageEnglish
Published England Elsevier B.V 06.08.2009
Subjects
Apoptosis
Apoptosis - drug effects
Caspase
Caspase Inhibitors
Caspases - metabolism
Cyclin-dependent kinase
Cyclin-Dependent Kinases - antagonists & inhibitors
Cyclin-Dependent Kinases - metabolism
Dose-Response Relationship, Drug
Down-Regulation
Eosinophil
Eosinophils - drug effects
Eosinophils - physiology
Eosinophils - ultrastructure
Humans
Inflammation
Mcl-1
Membrane Potential, Mitochondrial - physiology
Mitochondria
Myeloid Cell Leukemia Sequence 1 Protein
Protein Kinase Inhibitors - pharmacology
Proto-Oncogene Proteins c-bcl-2 - genetics
Proto-Oncogene Proteins c-bcl-2 - metabolism
Purines - pharmacology
R-roscovitine
Cyclin-dependent kinase
Mcl-1
Mitochondria
R-roscovitine
Caspase
Inflammation
Eosinophil
Apoptosis
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Summary:Eosinophils are major players in inflammatory allergic diseases such as asthma, hay fever and eczema. Here we show that the cyclin-dependent kinase inhibitor (CDKi) R-roscovitine efficiently and rapidly induces human eosinophil apoptosis using flow cytometric analysis of annexin-V/propidium iodide staining, morphological analysis by light microscopy, transmission electron microscopy and Western immunoblotting for caspase-3 cleavage. We further dissect these observations by demonstrating that eosinophils treated with R-roscovitine lose mitochondrial membrane potential and the key survival protein Mcl-1 is down-regulated. This novel finding of efficacious induction of eosinophil apoptosis by CDKi drugs has potential as a strategy for driving resolution of eosinophilic inflammation.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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ISSN:0014-5793
1873-3468
DOI:10.1016/j.febslet.2009.07.017