TNF/IL-1-inducible protein TSG-6 potentiates plasmin inhibition by inter-alpha-inhibitor and exerts a strong anti-inflammatory effect in vivo.
TNF/IL-1-inducible protein TSG-6 potentiates plasmin inhibition by inter-alpha-inhibitor and exerts a strong anti-inflammatory effect in vivo.
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DOI：
10.4049/jimmunol.156.4.1609
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发表时间：
1996-02
影响因子：
4.4
通讯作者：
H. Wisniewski;J. Hua;D. Poppers;Dwight Naime;J. Vilček;B. Cronstein
中科院分区：
文献类型：
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作者：
H. Wisniewski;J. Hua;D. Poppers;Dwight Naime;J. Vilček;B. Cronstein
TNF刺激基因6（tsg 6）编码35 kDa分泌糖蛋白（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TNF-α和IL-1或LPS诱导。在类风湿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间抑制剂（I α I）的组分形成稳定的复合物。在这项工作中，我们表明，TSG-6增强了抑制作用的l α 1纤溶酶的蛋白酶活性。纤溶酶/纤溶酶原激活物系统在与炎症相关的蛋白酶网络中是重要的。为了检验TSG-6和l α 1通过它们对纤溶酶的协同抑制作用可以调节蛋白酶网络并因此抑制炎症的假设，我们检查了TSG-6对实验诱导的炎症的作用。人重组TSG-6蛋白在角叉菜胶或IL-1诱导的急性炎症的小鼠气囊模型中显示出有效的抗炎活性。局部给药TSG-6对IL-1诱导的细胞浸润的抑制作用与全身地塞米松治疗相当。两个突变TSG-6蛋白与单一的氨基酸取代接近N端显示出完全或部分丧失抗炎活性。TNF/IL-1诱导型TSG-6蛋白的抗炎作用，沿着其通过与1 α 1相互作用抑制蛋白酶作用的能力，表明炎症期间的TSG-6产生是通过蛋白酶网络操作的负反馈环的一部分。
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.