Cook Andrew D, Braine Emma L, Campbell Ian K, Hamilton John A
Arthritis and Inflammation Research Center, University of Melbourne, Department of Medicine, Victoria, Australia.
Am J Pathol. 2002 Mar;160(3):917-26. doi: 10.1016/S0002-9440(10)64914-0.
The plasminogen activators, urokinase PA (u-PA) and tissue-type PA (t-PA), are believed to play important roles in inflammatory cell infiltration, fibrin deposition, and joint destruction associated with rheumatoid arthritis; however, their precise roles in such processes, particularly u-PA, have yet to be defined. Using gene-deficient mice we examined the relative contribution of the PAs to the chronic systemic collagen-induced arthritis model. Based on clinical and histological assessments, u-PA-/- mice developed significantly milder disease and t-PA-/- mice more severe disease compared with the relevant wild-type mice. Fibrin deposition within joints paralleled disease severity and was particularly pronounced in t-PA-/- mice. Likewise, cytokine levels in the synovium reflected the severity of disease, with interleukin-1beta levels in particular being lower in u-PA-/- mice and increased in t-PA-/- mice. The antibody response to type II collagen was normal in both knockouts; however, T cells from u-PA-/- mice had a reduced proliferative response and produced less interferon-gamma on antigen stimulation in vitro. These results indicate that the major effect of u-PA in the collagen-induced arthritis model is deleterious, whereas that of t-PA is protective. Our data highlight the complexities of PA function, and suggest that approaches either to target u-PA or to enhance local t-PA activity in joints may be of therapeutic benefit in rheumatoid arthritis.
纤溶酶原激活剂，即尿激酶型纤溶酶原激活剂（u-PA）和组织型纤溶酶原激活剂（t-PA），被认为在与类风湿性关节炎相关的炎症细胞浸润、纤维蛋白沉积和关节破坏中发挥重要作用；然而，它们在这些过程中的精确作用，尤其是u-PA的作用，尚未明确。我们使用基因缺陷小鼠研究了纤溶酶原激活剂对慢性系统性胶原诱导性关节炎模型的相对贡献。基于临床和组织学评估，与相关野生型小鼠相比，u-PA基因敲除小鼠的病情明显较轻，而t-PA基因敲除小鼠的病情更严重。关节内的纤维蛋白沉积与疾病严重程度平行，在t-PA基因敲除小鼠中尤为明显。同样，滑膜中的细胞因子水平反映了疾病的严重程度，特别是白细胞介素-1β水平在u-PA基因敲除小鼠中较低，而在t-PA基因敲除小鼠中升高。两种基因敲除小鼠对II型胶原的抗体反应均正常；然而，u-PA基因敲除小鼠的T细胞增殖反应降低，在体外抗原刺激下产生的干扰素-γ也较少。这些结果表明，在胶原诱导性关节炎模型中，u-PA的主要作用是有害的，而t-PA的作用是保护性的。我们的数据突出了纤溶酶原激活剂功能的复杂性，并表明靶向u-PA或增强关节局部t-PA活性的方法可能对类风湿性关节炎具有治疗益处。
