Treschow Alexandra P, Teige Ingrid, Nandakumar Kutty S, Holmdahl Rikard, Issazadeh-Navikas Shohreh
Section for Medical Inflammation Research, University of Lund, Lund, Sweden.
Arthritis Rheum. 2005 Dec;52(12):3739-48. doi: 10.1002/art.21496.
Clinical trials using interferon-beta (IFNbeta) in the treatment of rheumatoid arthritis have shown conflicting results. We undertook this study to understand the mechanisms of IFNbeta in arthritis at a physiologic level.
Collagen-induced arthritis (CIA) was induced in IFNbeta-deficient and control mice. The role of IFNbeta was investigated in both the priming and effector phases of the disease. The effect of IFNbeta deficiency on synovial cells, macrophages, and fibroblasts from preimmunized mice was analyzed by flow cytometry, immunohistochemistry, and enzyme-linked immunosorbent assay. Differences in osteoclast maturation were determined in situ by histology of arthritic and naive paws and by in vitro maturation studies of naive bone marrow cells. The importance of IFNbeta-producing fibroblasts was determined by transferring fibroblasts into mice at the time of CIA immunization.
Mice lacking IFNbeta had a prolonged disease with a higher incidence compared with control mice. IFNbeta deficiency was found to influence the effector phase, but not the priming phase, of arthritis. Compared with control mice, IFNbeta-deficient mice had greater infiltration of CD11b+ cells and greater production of tumor necrosis factor alpha in vivo, and their macrophages and fibroblasts were both more activated in vitro. Moreover, IFNbeta-deficient mice generated a greater number of osteoclasts in vitro, and mice immunized to induce arthritis, but not naive mice, had a greater number of osteoclasts in vivo compared with control mice. Importantly, IFNbeta-competent fibroblasts were able to ameliorate arthritis in IFNbeta-deficient recipients.
Our data indicate that IFNbeta is involved in regulating the activation state of osteoclasts and stromal cells, including macrophages and fibroblasts, but that it has little effect on T cells.
使用干扰素-β（IFNβ）治疗类风湿关节炎的临床试验结果相互矛盾。我们开展这项研究以在生理水平上了解IFNβ在关节炎中的作用机制。
在IFNβ缺陷小鼠和对照小鼠中诱导胶原诱导性关节炎（CIA）。在疾病的启动期和效应期研究IFNβ的作用。通过流式细胞术、免疫组织化学和酶联免疫吸附测定分析IFNβ缺陷对来自预先免疫小鼠的滑膜细胞、巨噬细胞和成纤维细胞的影响。通过关节炎和未免疫爪子的组织学以及未免疫骨髓细胞的体外成熟研究来确定破骨细胞成熟的差异。通过在CIA免疫时将成纤维细胞转移到小鼠体内来确定产生IFNβ的成纤维细胞的重要性。
与对照小鼠相比，缺乏IFNβ的小鼠疾病持续时间延长且发病率更高。发现IFNβ缺陷影响关节炎的效应期，但不影响启动期。与对照小鼠相比，IFNβ缺陷小鼠体内CD11b +细胞浸润更多，肿瘤坏死因子α产生更多，并且它们的巨噬细胞和成纤维细胞在体外均更活化。此外，IFNβ缺陷小鼠在体外产生更多的破骨细胞，并且与对照小鼠相比，免疫诱导关节炎的小鼠而非未免疫小鼠体内的破骨细胞数量更多。重要的是，具有IFNβ功能的成纤维细胞能够改善IFNβ缺陷受体中的关节炎。
我们的数据表明，IFNβ参与调节破骨细胞和基质细胞（包括巨噬细胞和成纤维细胞）的活化状态，但对T细胞影响很小。
