Inhibition of interleukin 1 (IL-1) binding and bioactivity in vitro and modulation of acute inflammation in vivo by IL-1 receptor antagonist and anti-IL-1 receptor monoclonal antibody.
Inhibition of interleukin 1 (IL-1) binding and bioactivity in vitro and modulation of acute inflammation in vivo by IL-1 receptor antagonist and anti-IL-1 receptor monoclonal antibody.
复制标题
IL-1受体拮抗剂和抗IL-1受体单克隆抗体在体外抑制白介素1（IL-1）结合和生物活性的体外调节。
DOI：
10.1084/jem.173.4.931
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发表时间：
1991-04-01
影响因子：
15.3
通讯作者：
Kilian, P L
中科院分区：
文献类型：
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作者：
McIntyre, K W;Stepan, G J;Kolinsky, K D;Benjamin, W R;Plocinski, J M;Kaffka, K L;Campen, C A;Chizzonite, R A;Kilian, P L
在体外和小鼠体内，检测了重组人白细胞介素 1 受体拮抗剂 (IL-1ra) 和 35F5（一种针对 I 型小鼠 IL-1 受体的中和单克隆抗体 (mAb)）与各种类型小鼠细胞上的 IL-1 受体 (IL-1R) 结合的能力，以及阻断对 IL-1 的免疫和炎症反应的能力。 IL-1ra竞争125I-IL-1α与表达重组小鼠I型IL-1R的EL-4胸腺瘤细胞、3T3成纤维细胞、肝细胞和中国仓鼠卵巢细胞上存在的I型IL-1R的结合。 IL-1ra 结合的 IC50 值（范围为 2 至 4 ng/ml）与 IL-1 α 相似。相反，IL-1ra以非常低的亲和力（IC50值范围为10至200微克/毫升）与表达II型IL-1R的细胞（即70Z/3前B细胞系和源自骨髓和急性炎症渗出物的多形核白细胞（PMN））结合。 mAb 35F5 特异性结合 I 型 IL-1R；使用非常高浓度的抗体没有观察到125I-IL-1α与具有II型IL-1R的细胞的结合受到抑制。虽然IL-1ra和35F5在使用T辅助D10.G4.1细胞和小鼠胸腺细胞的生物测定中均不具有内在活性，但这两种药物均阻断IL-1刺激这些细胞增殖的能力。还评估了 IL-1ra 和 35F5 对小鼠急性炎症反应的影响。腹腔注射rIL-1α后，IL-1ra和35F5阻断PMN的局部积累。当IL-1ra或35F5与IL-1同时或之前施用时，对IL-1的反应被抑制。腹腔注射脂多糖或蛋白胨后，IL-1ra 和 35F5 还可阻断 PMN 积聚，表明 IL-1 在介导对这些药物的反应中发挥重要作用。此外，IL-1ra和35F5显着阻断IL-1刺激PMN从骨髓中排出、诱导短暂性中性粒细胞增多以及升高肝急性期蛋白、IL-6和皮质酮的血清水平的能力。因此，IL-1ra和35F5在某些细胞类型上竞争性抑制IL-1与IL-1R的结合。这两种 IL-1 受体拮抗剂可抑制 IL-1 和其他炎症因子诱导的生物反应。
Recombinant human interleukin 1 receptor antagonist (IL-1ra) and 35F5, a neutralizing monoclonal antibody (mAb) to the type I mouse IL-1 receptor, were examined for their ability to bind to IL-1 receptors (IL- 1Rs) on various types of mouse cells and to block immune and inflammatory responses to IL-1 in vitro and in mice. IL-1ra competed for binding of 125I-IL-1 alpha to type I IL-1R present on EL-4 thymoma cells, 3T3 fibroblasts, hepatocytes, and Chinese hamster ovary cells expressing recombinant mouse type I IL-1R. The IC50 values for IL-1ra binding (ranging from 2 to 4 ng/ml) were similar to those of IL-1 alpha. In contrast, IL-1ra bound with very low affinity (IC50 values ranging from 10 to 200 micrograms/ml) to cells expressing type II IL- 1R, i.e., 70Z/3 pre-B cell line and polymorphonuclear leukocytes (PMN) derived from bone marrow and acute inflammatory exudates. The mAb 35F5 bound specifically to type I IL-1R; no inhibition of 125I-IL-1 alpha binding to cells having type II IL-1R was observed with very high concentrations of antibody. While neither IL-1ra nor 35F5 had intrinsic activity in bioassays using T helper D10.G4.1 cells and mouse thymocytes, both agents blocked the ability of IL-1 to stimulate proliferation of these cells. The effects of IL-1ra and 35F5 on acute inflammatory responses in mice were also evaluated. IL-1ra and 35F5 blocked the local accumulation of PMN after intraperitoneal injection of rIL-1 alpha. The response to IL-1 was inhibited when IL-1ra or 35F5 was administered simultaneously with or before administration of IL-1. IL-1ra and 35F5 also blocked PMN accumulation after intraperitoneal injection of lipopolysaccharide or proteose peptone, suggesting IL-1 is important in mediating responses to these agents. In addition, IL-1ra and 35F5 significantly blocked the ability of IL-1 to stimulate egress of PMN from bone marrow, to induce a transient neutrophilia, and to elevate serum levels of hepatic acute phase proteins, IL-6, and corticosterone. Thus, IL-1ra and 35F5 competitively inhibit the binding of IL-1 to the IL-1R on certain cell types. These two IL-1 receptor antagonists act to inhibit biological responses induced by IL-1 and other inflammatory agents.