hymenialdisine and Pleurisy

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.

Topics: Amino Acid Chloromethyl Ketones; Animals; Apoptosis; Azepines; Carrageenan; Caspase 3; Cyclin-Dependent Kinases; Enzyme Inhibitors; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Inflammation; Male; Mice; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasm Proteins; Neutrophils; Pleurisy; Proto-Oncogene Proteins c-bcl-2; Purines; Pyrroles; Roscovitine