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 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.
Duffin
Rodger
R
MRC Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh Medical School, Edinburgh, Scotland, UK.
Leitch
Andrew E
AE
Sheldrake
Tara A
TA
Hallett
John M
JM
Meyer
Colette
C
Fox
Sarah
S
Alessandri
Ana L
AL
Martin
Morag C
MC
Brady
Hugh J
HJ
Teixeira
Mauro M
MM
Dransfield
Ian
I
Haslett
Christopher
C
Rossi
Adriano G
AG
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
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