Rossi Adriano G, Sawatzky Deborah A, Walker Annemieke, Ward Carol, Sheldrake Tara A, Riley Nicola A, Caldicott Alison, Martinez-Losa Magdalena, Walker Trevor R, Duffin Rodger, Gray Mohini, Crescenzi Elvira, Martin Morag C, Brady Hugh J, Savill John S, Dransfield Ian, Haslett Christopher
MRC Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK.
Nat Med. 2006 Sep;12(9):1056-64. doi: 10.1038/nm1468. Epub 2006 Sep 3.
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.
细胞凋亡对于清除潜在有害的炎症细胞以及随后有效消除炎症至关重要。在此我们报告，人类中性粒细胞含有功能活跃的细胞周期蛋白依赖性激酶（CDK），并且结构多样的CDK抑制剂可诱导半胱天冬酶依赖性细胞凋亡，并克服来自诸如粒细胞-巨噬细胞集落刺激因子（GM-CSF）等存活因子的强大抗凋亡信号。我们表明，CDK抑制剂R-罗哌卡因（塞利西利或CYC202）在角叉菜胶诱发的急性胸膜炎、博来霉素诱导的肺损伤以及小鼠被动诱导的关节炎中，显著增强已建立的中性粒细胞依赖性炎症的消退。在胸膜炎模型中，半胱天冬酶抑制剂zVAD-fmk可阻止R-罗哌卡因增强的炎症消退，表明这种CDK抑制剂可增强炎症细胞凋亡。我们还提供证据表明，R-罗哌卡因通过降低抗凋亡蛋白Mcl-1的浓度来促进细胞凋亡。因此，CDK抑制剂通过促进炎症细胞凋亡来增强已建立炎症的消退，从而证明了其在治疗炎症性疾病方面迄今未被认识到的潜力。
