Cyclin-dependent kinase inhibitors enhance the resolution of inflammation by promoting inflammatory cell apoptosis
| Autor: | Morag C. Martin, Annemieke Walker, Rodger Duffin, Deborah A. Sawatzky, Adriano G. Rossi, Trevor R. Walker, Elvira Crescenzi, Alison Caldicott, Christopher Haslett, Nicola A. Riley, Tara A. Sheldrake, Ian Dransfield, Mohini Gray, John Savill, Hugh J.M. Brady, Magdalena Martinez-Losa, Carol Ward |
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| Jazyk: | angličtina |
| Rok vydání: | 2006 |
| Předmět: |
Male
Neutrophils Cell Apoptosis Inflammation Lung injury Carrageenan General Biochemistry Genetics and Molecular Biology Amino Acid Chloromethyl Ketones Mice chemistry.chemical_compound Cyclin-dependent kinase Roscovitine medicine Animals Humans Pyrroles NF-KAPPA-B HUMAN NEUTROPHILS IN-VIVO DOWN-REGULATION R-ROSCOVITINE BACTERIAL LIPOPOLYSACCHARIDE INDUCIBLE CYCLOOXYGENASE SELICICLIB CYC202 AGING NEUTROPHILS MULTIPLE-MYELOMA Enzyme Inhibitors Pleurisy Seliciclib biology Caspase 3 Kinase business.industry Granulocyte-Macrophage Colony-Stimulating Factor Azepines General Medicine Cyclin-Dependent Kinases Neoplasm Proteins medicine.anatomical_structure Proto-Oncogene Proteins c-bcl-2 chemistry Purines Immunology Cancer research biology.protein Myeloid Cell Leukemia Sequence 1 Protein medicine.symptom business CDK inhibitor |
| Zdroj: | Nature medicine 12 (2006): 1056–1064. doi:10.1038/nm1468 info:cnr-pdr/source/autori:Rossi AG; Sawatzky DA; Walker A; Ward C; Sheldrake TA; Riley NA; Caldicott A; Martinez-Losa M; Walker TR; Duffin R; Gray M; Crescenzi E; Martin MC; Brady HJ; Savill JS; Dransfield I; Haslett C./titolo:Cyclin-dependent kinase inhibitors enhance the resolution of inflammation by promoting inflammatory cell apoptosis/doi:10.1038%2Fnm1468/rivista:Nature medicine (Print)/anno:2006/pagina_da:1056/pagina_a:1064/intervallo_pagine:1056–1064/volume:12 |
| DOI: | 10.1038/nm1468 |
| Popis: | 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, bleomycininduced 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. |
| Databáze: | OpenAIRE |
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