title: Cyclin-dependent kinase inhibitors enhance the resolution of inflammation by promoting inflammatory cell apoptosis.
abstract: 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.
authors.affiliation: 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
authors.forename: Adriano G
authors.initials: AG
authors.lastname: Rossi
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Sawatzky
authors.forename: Annemieke
authors.initials: A
authors.lastname: Walker
authors.forename: Carol
authors.initials: C
authors.lastname: Ward
authors.forename: Tara A
authors.initials: TA
authors.lastname: Sheldrake
authors.forename: Nicola A
authors.initials: NA
authors.lastname: Riley
authors.forename: Alison
authors.initials: A
authors.lastname: Caldicott
authors.forename: Magdalena
authors.initials: M
authors.lastname: Martinez-Losa
authors.forename: Trevor R
authors.initials: TR
authors.lastname: Walker
authors.forename: Rodger
authors.initials: R
authors.lastname: Duffin
authors.forename: Mohini
authors.initials: M
authors.lastname: Gray
authors.forename: Elvira
authors.initials: E
authors.lastname: Crescenzi
authors.forename: Morag C
authors.initials: MC
authors.lastname: Martin
authors.forename: Hugh J
authors.initials: HJ
authors.lastname: Brady
authors.forename: John S
authors.initials: JS
authors.lastname: Savill
authors.forename: Ian
authors.initials: I
authors.lastname: Dransfield
authors.forename: Christopher
authors.initials: C
authors.lastname: Haslett
mesh_terms: 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
chemical_list: 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