Inhibition of lipopolysaccharide-mediated human monocyte activation, in vitro, by α1-antitrypsin
Inhibition of lipopolysaccharide-mediated human monocyte activation, in vitro, by α1-antitrypsin
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DOI：
10.1016/j.bbrc.2004.06.123
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发表时间：
2004-08-27
影响因子：
3.1
通讯作者：
Stevens, T
中科院分区：
文献类型：
--
作者：
Janciauskiene, S;Larsson, S;Stevens, T
α 1-抗胰蛋白酶（AAT）是丝氨酸蛋白酶的主要循环和组织抑制剂。因此，AAT被认为在限制炎症部位的宿主组织损伤中起重要作用。然而，现在有越来越多的证据表明，AAT可能表现出独立于其蛋白酶抑制剂功能的生物活性。在这项研究中，我们比较了天然（抑制性）和修饰（非抑制性）的效果，例如，聚合和氧化形式的AAT对LPS诱导的人单核细胞活化的影响。我们发现，天然AAT抑制LPS刺激的TNF α和IL-1 β mRNA和蛋白质的合成和释放，但增强抗炎细胞因子IL-10的释放。类似地，AAT的聚合和氧化形式抑制LPS刺激的1 L-1 β和TNF α。无论是在去除LPS之前还是之后加入，都观察到AAT的作用，这表明激动剂的螯合不太可能解释其生物学效应。此外，中和抗体研究表明，IL-10的产生不太可能是AAT抑制作用的机制。因此，我们的数据首次证明AAT在体外表现出与丝氨酸蛋白酶抑制无关的抗炎活性。(C)2004年爱思唯尔公司All rights reserved.
alpha1-Antitrypsin (AAT) is a major circulating and tissue inhibitor of serine proteinases. As such AAT is thought to play an important role in limiting host tissue injury at sites of inflammation. There is now increasing evidence, however, that AAT may exhibit biological activity independent of its protease inhibitor function. In this study we compared the effects of native (inhibitory) and modified (non-inhibitory), e.g., polymerised and oxidised forms of AAT on LPS-induced human monocyte activation, in vitro. We found that native AAT inhibited LPS-stimulated synthesis and release of TNFalpha and IL-1beta mRNA and protein, respectively, but enhanced the release of the anti-inflammatory cytokine, IL-10. Similarly, polymerised and oxidised forms of AAT inhibited LPS-stimulated 1L-1beta and TNFalpha. The effects of AATs were observed whether added prior to or following removal of LPS, suggesting that sequestration of agonist was unlikely to explain their biological effects. Furthermore, studies with neutralising antibodies indicated that generation of IL-10 was unlikely to be the mechanism responsible for the inhibitory effects of AATs. Thus, our data demonstrate for the first time that AAT exhibits anti-inflammatory activity in vitro that is unrelated to inhibition of serine proteases. (C) 2004 Elsevier Inc. All rights reserved.