Cyclin-dependent kinase inhibitors enhance the resolution of inflammation by promoting inflammatory cell apoptosis.
Apoptosis is essential for clearance of potentially injurious inflammatory cells and subsequent efficient resolution of inflammation. Here we report that human neutrophils contain functionally active cyclin-dependent kinases (CDKs), and that structurally diverse CDK inhibitors induce caspase-dependent apoptosis and override powerful anti-apoptosis signals from survival factors such as granulocyte-macrophage colony-stimulating factor (GM-CSF). We show that the CDK inhibitor R-roscovitine (Seliciclib or CYC202) markedly enhances resolution of established neutrophil-dependent inflammation in carrageenan-elicited acute pleurisy, bleomycin-induced lung injury, and passively induced arthritis in mice. In the pleurisy model, the caspase inhibitor zVAD-fmk prevents R-roscovitine-enhanced resolution of inflammation, indicating that this CDK inhibitor augments inflammatory cell apoptosis. We also provide evidence that R-roscovitine promotes apoptosis by reducing concentrations of the anti-apoptotic protein Mcl-1. Thus, CDK inhibitors enhance the resolution of established inflammation by promoting apoptosis of inflammatory cells, thereby demonstrating a hitherto unrecognized potential for the treatment of inflammatory disorders.
Rossi
Adriano G
AG
MRC Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK. a.g.rossi@ed.ac.uk
Sawatzky
Deborah A
DA
Walker
Annemieke
A
Ward
Carol
C
Sheldrake
Tara A
TA
Riley
Nicola A
NA
Caldicott
Alison
A
Martinez-Losa
Magdalena
M
Walker
Trevor R
TR
Duffin
Rodger
R
Gray
Mohini
M
Crescenzi
Elvira
E
Martin
Morag C
MC
Brady
Hugh J
HJ
Savill
John S
JS
Dransfield
Ian
I
Haslett
Christopher
C
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001381:Azepines / Q000494:pharmacology; D002351:Carrageenan; D053148:Caspase 3 / Q000502:physiology; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000188:drug therapy*; D008297:Male; D051379:Mice; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000096:biosynthesis; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D010998:Pleurisy / Q000139:chemically induced / Q000188:drug therapy; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D011687:Purines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D000077546:Roscovitine
D000590:Amino Acid Chloromethyl Ketones; D001381:Azepines; D004791:Enzyme Inhibitors; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011687:Purines; D011758:Pyrroles; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D000077546:Roscovitine; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D002351:Carrageenan; C107079:hymenialdisine; D018844:Cyclin-Dependent Kinases; D053148:Caspase 3