Limper A H, Edens M, Anders R A, Leof E B
Thoracic Diseases Research Unit, Division of Pulmonary, Critical Care, and Internal Medicine, Department of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.
J Clin Invest. 1998 Mar 1;101(5):1148-55. doi: 10.1172/JCI659.
Pneumocystis carinii remains an important cause of pneumonia in patients with AIDS. Attachment of the organism to epithelial cells is a central event in establishing infection, impairing the growth potential of lung epithelial cells and thereby slowing repair. In light of investigations documenting a central role for cyclin-dependent kinases in controlling the cell cycle, we addressed the hypothesis that P. carinii inhibits epithelial cell growth by interfering with host epithelial cyclin-dependent kinase (cdk) activity. We observed that P. carinii significantly impaired growth of cultured mink lung epithelial cells, with effects observed after 48-72 h of treatment. However, the kinase activity associated with p34cdc2 or p33cdk2 was maximally inhibited as early as 24 h after P. carinii exposure. The inhibitory effect on cyclin-dependent kinase activity was mediated by the trophozoite form of P. carinii, in that highly purified trophozoites exerted marked inhibition of p34cdc2 activity. Growth impairment was similarly preceded by P. carinii-induced alteration in the state of epithelial cell p34cdc2 phosphorylation, with no change in p34cdc2 or p33cdk2 protein levels. These data strongly suggest that the antiproliferative activity of P. carinii on respiratory epithelium is mediated in part through modulation of the host cell cycle machinery.
卡氏肺孢子菌仍然是艾滋病患者肺炎的一个重要病因。该病原体附着于上皮细胞是建立感染的核心事件，会损害肺上皮细胞的生长潜能，从而延缓修复。鉴于有研究记录了细胞周期蛋白依赖性激酶在控制细胞周期中的核心作用，我们探讨了卡氏肺孢子菌通过干扰宿主上皮细胞周期蛋白依赖性激酶（cdk）活性来抑制上皮细胞生长的假说。我们观察到，卡氏肺孢子菌显著损害培养的水貂肺上皮细胞的生长，在处理48 - 72小时后观察到这种影响。然而，与p34cdc2或p33cdk2相关的激酶活性早在卡氏肺孢子菌暴露后24小时就受到最大程度的抑制。对细胞周期蛋白依赖性激酶活性的抑制作用是由卡氏肺孢子菌的滋养体形式介导的，因为高度纯化的滋养体对p34cdc2活性有显著抑制作用。在生长受损之前，同样出现了卡氏肺孢子菌诱导的上皮细胞p34cdc2磷酸化状态的改变，而p34cdc2或p33cdk2蛋白水平没有变化。这些数据强烈表明，卡氏肺孢子菌对呼吸道上皮的抗增殖活性部分是通过调节宿主细胞周期机制介导的。
