title: The CDK inhibitor, R-roscovitine, promotes eosinophil apoptosis by down-regulation of Mcl-1.
abstract: 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.
authors.affiliation: MRC Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh Medical School, Edinburgh, Scotland, UK.
authors.forename: Rodger
authors.initials: R
authors.lastname: Duffin
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Leitch
authors.forename: Tara A
authors.initials: TA
authors.lastname: Sheldrake
authors.forename: John M
authors.initials: JM
authors.lastname: Hallett
authors.forename: Colette
authors.initials: C
authors.lastname: Meyer
authors.forename: Sarah
authors.initials: S
authors.lastname: Fox
authors.forename: Ana L
authors.initials: AL
authors.lastname: Alessandri
authors.forename: Morag C
authors.initials: MC
authors.lastname: Martin
authors.forename: Hugh J
authors.initials: HJ
authors.lastname: Brady
authors.forename: Mauro M
authors.initials: MM
authors.lastname: Teixeira
authors.forename: Ian
authors.initials: I
authors.lastname: Dransfield
authors.forename: Christopher
authors.initials: C
authors.lastname: Haslett
authors.forename: Adriano G
authors.initials: AG
authors.lastname: Rossi
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004804:Eosinophils / Q000187:drug effects* / Q000502:physiology / Q000648:ultrastructure; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D011687:Purines / Q000494:pharmacology*; D000077546:Roscovitine
chemical_list: D061945:Caspase Inhibitors; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011687:Purines; D000077546:Roscovitine; D018844:Cyclin-Dependent Kinases; D020169:Caspases