TSG-6 potentiates the antitissue kallikrein activity of inter-α-inhibitor through bikunin release
TSG-6 potentiates the antitissue kallikrein activity of inter-α-inhibitor through bikunin release
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DOI：
10.1165/rcmb.2006-0018oc
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发表时间：
2007-01-01
影响因子：
6.4
通讯作者：
Day, Anthony J.
中科院分区：
文献类型：
--
作者：
Forteza, Rosanna;Casalino-Matsuda, Susana M.;Day, Anthony J.
TSG-6（TNF-刺激基因-6的蛋白产物）是一种炎症相关蛋白，与来自α-抑制剂间和α-抑制剂前的重链（HC）形成共价复合物，并与其共同的bikunin链非共价缔合，增强这种丝氨酸蛋白酶抑制剂的抗纤溶酶活性。结果表明，TSG-6和TSG-6（.）HC复合物存在于哮喘患者的支气管肺泡灌洗液中，并在变应原激发后增加。免疫检测显示吸烟者气道组织和分泌物中TSG-6升高。用纯化的组分进行的体外实验显示bikunin.HC复合物（TSG-6.HC形成的副产物）释放bikunin。免疫沉淀显示，bikunin占过敏原激发后支气管肺泡灌洗液中组织激肽释放酶抑制的显著比例，但在基线条件下则不然，证实游离状态的bikunin是气道分泌物中的相关蛋白酶抑制剂，但与HC相关时则不然。在分化的人气道上皮和粘膜下腺细胞的原代培养物中，TSG-6由TNF-α和IL-1 β诱导，这表明这些细胞负责体内TSG-6的释放。Bikunin和HC 3（即，前α-抑制剂）也在原代培养物中被TNF-α诱导。我们的研究结果表明，TSG-6可能发挥重要的保护作用，支气管上皮细胞通过增加气道腔的抗蛋白酶屏幕。
TSG-6 (the protein product of TNF-stimulated gene-6), an inflammation-associated protein, forms covalent complexes with heavy chains (HCs) from inter-alpha-inhibitor and pre-alpha-inhibitor and associates noncovalently with their common bikunin chain, potentiating the antiplasmin activity of this serine protease inhibitor. We show that TSG-6 and TSG-6(.)HC complexes are present in bronchoalveolar lavage fluid from patients with asthma and increase after allergen challenge. Immunodetection demonstrated elevated TSG-6 in the airway tissue and secretions of smokers. Experiments conducted in vitro with purified components revealed that bikunin.HC complexes (byproducts of TSG-6.HC formation) release bikunin. Immunoprecipitation revealed that bikunin accounts for a significant proportion of tissue kallikrein inhibition in bronchoalveolar lavage after allergen challenge but not in baseline conditions, confirming that bikunin in its free state, but not when associated with HCs, is a relevant protease inhibitor in airway secretions. In primary cultures of differentiated human airway epithelial and submucosal gland cells, TSG-6 is induced by TNF-alpha and IL-1 beta, which suggests that these cells are responsible for TSG-6 release in vivo. Bikunin and HC3 (i.e., pre-alpha-inhibitor) were also induced by TNF-alpha in primary cultures. Our results suggest that TSG-6 may play an important protective role in bronchial epithelium by increasing the antiprotease screen on the airway lumen.