Janciauskiene Sabina, Zelvyte Inga, Jansson Lennart, Stevens Tim
Department of Medicine, University Hospital Malmö, Malmö, S-20502, Sweden.
Biochem Biophys Res Commun. 2004 Mar 5;315(2):288-96. doi: 10.1016/j.bbrc.2004.01.055.
alpha1-Antitrypsin (AAT) is a major circulating serine proteinase inhibitor in humans. The anti-proteinase activity of AAT is inhibited by chemical modification. These include inter- or intramolecular polymerisation, oxidation, complex formation with target proteinases (e.g., neutrophil elastase), and/or cleavage by multi-specific proteinases. In vivo, several modified forms of AAT have been identified which stimulate biological activity in vitro unrelated to inhibition of serine proteinases. In this study we have examined the effects of native and polymerised AAT and C-36 peptide, a proteolytic cleavage product of AAT, on human neutrophil activation, in vitro. We show that the C-36 peptide displays striking concentration-dependent pro-inflammatory effects on human neutrophils, including induction of neutrophil chemotaxis, adhesion, degranulation, and superoxide generation. In contrast to C-36 peptide, native and polymerised AAT at similar and higher concentrations showed no effects on neutrophil activation. These results suggest that cleavage of AAT may not only abolish its proteinase inhibitor activity, but can also generate a powerful pro-inflammatory activator for human neutrophils.
α1-抗胰蛋白酶（AAT）是人体内主要的循环丝氨酸蛋白酶抑制剂。AAT的抗蛋白酶活性会受到化学修饰的抑制。这些修饰包括分子间或分子内聚合、氧化、与靶蛋白酶（如中性粒细胞弹性蛋白酶）形成复合物，和/或被多特异性蛋白酶切割。在体内，已鉴定出几种AAT的修饰形式，它们在体外可刺激与丝氨酸蛋白酶抑制无关的生物活性。在本研究中，我们在体外检测了天然和聚合的AAT以及AAT的蛋白水解切割产物C-36肽对人中性粒细胞活化的影响。我们发现C-36肽对人中性粒细胞表现出显著的浓度依赖性促炎作用，包括诱导中性粒细胞趋化、黏附、脱颗粒和超氧化物生成。与C-36肽相反，相似浓度及更高浓度的天然和聚合AAT对中性粒细胞活化没有影响。这些结果表明，AAT的切割不仅可能消除其蛋白酶抑制剂活性，还可能产生一种强大的人中性粒细胞促炎激活剂。
