Robson S C, Saunders R, Kirsch R E
Department of Medicine, University of Cape Town, Observatory, Republic of South Africa.
J Clin Lab Immunol. 1990 Oct;33(2):83-90.
Interleukin-1 (IL-1) release from monocyte-macrophages (Mo) appears dependent on pericellular proteolysis mediated by plasmin. Thus plasminogen activator inhibitors (PAI) which bind the serine proteases responsible for the conversion of plasminogen to plasmin, may inhibit IL-1 release from Mo. We have examined the effect of purified PAI from a hepatoma cell line Hep G2, on IL-1 release from Mo with secondary effects on lymphocyte proliferation in vitro. Fast acting inhibitors of both urokinase (u-PA) and tissue plasminogen activator (two chain t-PA) were noted in harvest fluids of Hep G2 cells. These inhibitors were stable at pH 3 but lost activity at 45 degrees C. They were SDS-stable and migrated with Mr53 and 104 kDa. These properties conformed to characteristics of type-1 plasminogen activator inhibitor (PAI-1). Partially purified PAI-1 added to human Mo cultured on 125I fibrin layer both in the presence and absence of plasminogen inhibited secretion of IL-1 by Mo in response to LPS. This effect, however, did not correlate with the inhibition of plasminogen dependent fibrinolysis. This suggested a degree of sequestration and inaccessibility of membrane bound u-PA of LPS activated Mo to PAI-1. PAI-1, in addition, inhibited mitogen stimulated peripheral blood mononuclear cell (PBMC) proliferation at similar concentration ranges. This effect was abrogated by the addition of specific antisera to PAI-1. PAI-1 may be released as part of an acute phase response. In addition to influencing fibrinolysis, PAI-1 may constitute a negative feedback pathway on Mo IL-1 release and subsequent immune activation in vivo.
单核巨噬细胞（Mo）释放白细胞介素-1（IL-1）似乎依赖于纤溶酶介导的细胞周缘蛋白水解作用。因此，与负责将纤溶酶原转化为纤溶酶的丝氨酸蛋白酶结合的纤溶酶原激活物抑制剂（PAI），可能会抑制Mo释放IL-1。我们研究了从肝癌细胞系Hep G2中纯化得到的PAI对Mo释放IL-1的影响，以及其对体外淋巴细胞增殖的继发作用。在Hep G2细胞的收获液中发现了对尿激酶（u-PA）和组织纤溶酶原激活物（双链t-PA）均有快速作用的抑制剂。这些抑制剂在pH 3时稳定，但在45℃时失活。它们对十二烷基硫酸钠（SDS）稳定，分子量分别为53 kDa和104 kDa。这些特性符合1型纤溶酶原激活物抑制剂（PAI-1）的特征。在存在和不存在纤溶酶原的情况下，将部分纯化的PAI-1添加到培养在125I纤维蛋白层上的人Mo中，可抑制Mo对脂多糖（LPS）刺激的IL-1分泌。然而，这种作用与对纤溶酶原依赖性纤维蛋白溶解的抑制并无关联。这表明LPS激活的Mo膜结合u-PA存在一定程度被隔离且PAI-1难以接近的情况。此外，PAI-1在相似浓度范围内可抑制有丝分裂原刺激的外周血单个核细胞（PBMC）增殖。添加针对PAI-1的特异性抗血清可消除这种作用。PAI-1可能作为急性期反应的一部分被释放。除了影响纤维蛋白溶解外，PAI-1可能在体内构成对Mo释放IL-1及随后免疫激活的负反馈途径。
