A murine transmembrane tumor necrosis factor (TNF) transgene induces arthritis by cooperative p55/p75 TNF receptor signaling
A murine transmembrane tumor necrosis factor (TNF) transgene induces arthritis by cooperative p55/p75 TNF receptor signaling
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DOI：
10.1002/eji.1830271018
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发表时间：
1997-10-01
影响因子：
5.4
通讯作者：
Kollias, G
中科院分区：
文献类型：
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作者：
Alexopoulou, L;Pasparakis, M;Kollias, G
在关节炎的实验动物模型中，以及在关节表达野生型或突变型人肿瘤坏死因子蛋白的转基因小鼠中，肿瘤坏死因子及其p55肿瘤坏死因子受体(R)的致关节炎活性已被很好地证明。在这项研究中，我们表明慢性炎症性关节炎也发生在转基因小鼠身上，转基因小鼠过度表达突变的跨膜形式的小鼠肿瘤坏死因子蛋白(muTNF(Delta 1-12))，已知这种蛋白有效地利用了p55和p75TNFR。将转基因杂交到肿瘤坏死因子基因敲除背景中并没有改变疾病的发展。对脂多糖刺激的小鼠和体外巨噬细胞培养的血清中肿瘤坏死因子的生物活性分析表明，muTNF(Delta 1-12)蛋白聚集在细胞表面，不被加工成具有生物活性的可溶性肿瘤坏死因子，表明跨膜型肿瘤坏死因子本身足以介导关节炎的发病。此外，利用TNFR基因敲除小鼠的研究表明，跨膜性肿瘤坏死因子介导的关节炎的发展需要p55TNFR的存在，但在缺乏p75TNFR的情况下显著延迟，这表明两种TNFR在关节形成过程中存在积极的合作。这些结果表明，阻断可溶性肿瘤坏死因子和跨膜肿瘤坏死因子的活性可能是有效中和这种细胞因子在关节炎中的致病潜力所必需的。
The arthritogenic activities of tumor necrosis factor (TNF) and its p55TNF-receptor (R) have been well documented in experimental animal models of arthritis, and in transgenic mice expressing wild-type or mutant transmembrane human TNF proteins in their joints. In this study we show that chronic inflammatory arthritis also develops in transgenic mice made to overexpress a mutant transmembrane from of the murine TNF protein (muTNF(Delta 1-12)) which is known to utilize efficiently both the p55 and the p75TNFR. Cross-breeding of the transgene into a TNF knockout background did not alter development of disease. Analysis of TNF bioactivity in sera from lipopolysaccharide-stimulated mice or ex vivo macrophage cultures demonstrated that the muTNF(Delta 1-12) protein accumulates on the cell surface and is not processed to bioactive soluble TNF, indicating that transmembrane TNF is by itself sufficient to mediate pathogenesis of arthritis. Furthermore, using TNFR knockout mice, it is shown that development of transmembrane TNF-mediated arthritis requires the presence of the p55TNFR but is significantly delayed in the absence of the p75TNFR, suggesting a positive cooperation between the two TNFR in the arthritogenic process. These results indicate that blocking the activities of both soluble and transmembrane TNF may be required to effectively neutralize the pathogenic potential of this cytokine in arthritis.