Prevot Pierre-Paul, Beschin Alain, Lins Laurence, Beaufays Jérôme, Grosjean Amélie, Bruys Léa, Adam Benoît, Brossard Michel, Brasseur Robert, Zouaoui Boudjeltia Karim, Vanhamme Luc, Godfroid Edmond
Laboratoire de Biologie Moléculaire des Ectoparasites, Université Libre de Bruxelles, Gosselies, Belgium.
FEBS J. 2009 Jun;276(12):3235-46. doi: 10.1111/j.1742-4658.2009.07038.x. Epub 2009 Apr 29.
Serine protease inhibitors (serpins) are a structurally related but functionally diverse family of ubiquitous proteins. We previously described Ixodes ricinus immunosuppressor (Iris) as a serpin from the saliva of the tick I. ricinus displaying high affinity for human leukocyte elastase. Iris also displays pleotropic effects because it interferes with both the immune response and hemostasis of the host. It thus inhibits lymphocyte proliferation and the secretion of interferon-gamma or tumor necrosis factor-alpha by peripheral blood mononuclear cells, and also platelet adhesion, coagulation and fibrinolysis. Its ability to interfere with coagulation and fibrinolysis, but not platelet adhesion, depends on the integrity of its antiproteolytic reactive center loop domain. Here, we dissect the mechanisms underlying the interaction of recombinant Iris with peripheral blood mononuclear cells. We show that Iris binds to monocytes/macrophages and inhibits their ability to secrete tumor necrosis factor-alpha. Recombinant Iris also has a protective role in endotoxemic shock. The anti-inflammatory ability of Iris does not depend on its antiprotease activity. Moreover, we pinpoint the exosites involved in this activity.
丝氨酸蛋白酶抑制剂（丝氨酸蛋白酶抑制剂家族）是一类结构相关但功能多样的普遍存在的蛋白质。我们之前将蓖麻蜱免疫抑制剂（Iris）描述为蓖麻蜱唾液中的一种丝氨酸蛋白酶抑制剂，它对人白细胞弹性蛋白酶具有高亲和力。Iris还具有多效性，因为它会干扰宿主的免疫反应和止血过程。因此，它抑制淋巴细胞增殖以及外周血单核细胞分泌γ干扰素或肿瘤坏死因子-α，还抑制血小板黏附、凝血和纤维蛋白溶解。它干扰凝血和纤维蛋白溶解（但不干扰血小板黏附）的能力取决于其抗蛋白水解反应中心环结构域的完整性。在这里，我们剖析重组Iris与外周血单核细胞相互作用的潜在机制。我们发现Iris与单核细胞/巨噬细胞结合并抑制它们分泌肿瘤坏死因子-α的能力。重组Iris在内毒素性休克中也具有保护作用。Iris的抗炎能力不依赖于其抗蛋白酶活性。此外，我们确定了参与此活性的外部结合位点。
