Wisniewski H G, Hua J C, Poppers D M, Naime D, Vilcek J, Cronstein B N
Department of Microbiology, Kaplan Cancer Center, New York University Medical Center, NY 10016, USA.
J Immunol. 1996 Feb 15;156(4):1609-15.
TNF-stimulated gene 6 (tsg6), encoding a 35-kDa secretory glycoprotein (TSG-6), is induced in fibroblasts, chondrocytes, synovial cells, and mononuclear cells by the proinflammatory cytokines TNF-alpha and IL-1, or by LPS. Large amounts of TSG-6 protein were found in synovial fluids of patients with rheumatoid arthritis. TSG-6 protein forms a stable complex with components of the serine protease inhibitor, inter-alpha-inhibitor (I alpha I). In this work, we show that TSG-6 potentiates the inhibitory effect of l alpha l on the protease activity of plasmin. The plasmin/plasminogen activator system is important in the protease network associated with inflammation. To test the hypothesis that through their cooperative inhibitory effect on plasmin TSG-6 and l alpha l can modulate the protease network and thus inhibit inflammation, we examined the effect of TSG-6 on experimentally induced inflammation. Human recombinant TSG-6 protein showed a potent anti-inflammatory activity in the murine air pouch model of carrageenan- or IL-1-induced acute inflammation. The inhibitory effect of locally administered TSG-6 on the IL-1-induced cellular infiltration was comparable with that of systemic dexamethasone treatment. Two mutant TSG-6 proteins with single amino acid substitutions close to the N terminus showed a complete or partial loss of anti-inflammatory activity. The anti-inflammatory effect of the TNF/IL-1-inducible TSG-6 protein, along with its ability to inhibit protease action through interaction with l alpha l, suggests that TSG-6 production during inflammation is part of a negative feedback loop operating through the protease network.
肿瘤坏死因子刺激基因6（tsg6）编码一种35kDa的分泌性糖蛋白（TSG-6），在成纤维细胞、软骨细胞、滑膜细胞和单核细胞中，由促炎细胞因子肿瘤坏死因子-α和白细胞介素-1或脂多糖诱导产生。在类风湿性关节炎患者的滑液中发现了大量的TSG-6蛋白。TSG-6蛋白与丝氨酸蛋白酶抑制剂α-抑制因子（IαI）的成分形成稳定复合物。在这项研究中，我们表明TSG-6增强了IαI对纤溶酶蛋白酶活性的抑制作用。纤溶酶/纤溶酶原激活剂系统在与炎症相关的蛋白酶网络中起重要作用。为了验证通过对纤溶酶的协同抑制作用，TSG-6和IαI可以调节蛋白酶网络从而抑制炎症这一假说，我们研究了TSG-6对实验性诱导炎症的影响。人重组TSG-6蛋白在角叉菜胶或白细胞介素-1诱导的急性炎症小鼠气袋模型中显示出强大的抗炎活性。局部施用TSG-6对白细胞介素-1诱导的细胞浸润的抑制作用与全身地塞米松治疗相当。两种在靠近N端有单个氨基酸取代的突变TSG-6蛋白显示出完全或部分抗炎活性丧失。TNF/IL-1诱导的TSG-6蛋白的抗炎作用，以及其通过与IαI相互作用抑制蛋白酶作用的能力，表明炎症期间TSG-6的产生是通过蛋白酶网络运行的负反馈回路的一部分。
