Netea M G, Kullberg B J, Boerman O C, Verschueren I, Dinarello C A, Van der Meer J W
Division of General Internal Medicine, Department of Medicine and Nuclear Medicine, University Hospital Nijmegen, The Netherlands.
J Immunol. 1999 Apr 15;162(8):4876-81.
IL-1 alpha and IL-1 beta are proinflammatory cytokines involved in the pathogenesis of many infectious and noninfectious inflammatory diseases. To reduce IL-1 toxicity, extracellular domains of the soluble (s) IL-1R are shed from cell membranes and prevent triggering of cell-bound receptors. We investigated to what extent murine sIL-1RI can neutralize the IL-1 produced by LPS-stimulated macrophages. When mouse peritoneal macrophages were incubated with LPS, addition of sIL-1RI significantly inhibited the bioactivity of IL-1. Stimulation of cells with sIL-1RI alone induced no bioactive IL-1. When immunoreactive cytokine concentrations were measured with specific radioimmunoassays, sIL-1RI alone appeared to induce a significant release of IL-1 alpha in a concentration-dependent manner. This effect was independent of new protein synthesis. The production of IL-1 beta or TNF-alpha was not influenced by sIL-1RI. There was no interference of sIL-1RI with the IL-1 alpha radioimmunoassay. In mice, an i.v. injection of sIL-RI alone induced a rapid release of IL-1 alpha, but not of TNF-alpha or IL-1 beta. Treatment of mice with sIL-1RI improved the survival during a lethal infection with Candida albicans. In conclusion, sIL-1RI induces a rapid release of IL-1 alpha from cells, as well as into the systemic circulation. Although this IL-1 alpha may be inactivated in circulation by the same sIL-1RI, this phenomenon probably has immunostimulatory effects at local levels where the sIL-1RI-induced IL-1 alpha acts in a paracrine or autocrine manner.
白细胞介素-1α（IL-1α）和白细胞介素-1β（IL-1β）是促炎细胞因子，参与多种感染性和非感染性炎症疾病的发病机制。为降低IL-1的毒性，可溶性（s）IL-1受体的细胞外结构域从细胞膜上脱落，从而防止细胞结合受体被激活。我们研究了小鼠sIL-1RI在多大程度上能够中和脂多糖（LPS）刺激的巨噬细胞产生的IL-1。当小鼠腹腔巨噬细胞与LPS一起孵育时，添加sIL-1RI可显著抑制IL-1的生物活性。单独用sIL-1RI刺激细胞不会诱导产生有生物活性的IL-1。当用特异性放射免疫测定法测量免疫反应性细胞因子浓度时，单独的sIL-1RI似乎以浓度依赖的方式诱导IL-1α显著释放。这种效应与新的蛋白质合成无关。sIL-1RI不影响IL-1β或肿瘤坏死因子-α（TNF-α）的产生。sIL-1RI对IL-1α放射免疫测定没有干扰。在小鼠中，静脉注射单独的sIL-RI可诱导IL-1α快速释放，但不会诱导TNF-α或IL-1β释放。用sIL-1RI治疗小鼠可提高其在白色念珠菌致死性感染期间的存活率。总之，sIL-1RI可诱导细胞快速释放IL-1α，并释放到体循环中。尽管这种IL-1α可能在循环中被相同的sIL-1RI灭活，但这种现象可能在局部水平具有免疫刺激作用，其中sIL-1RI诱导的IL-1α以旁分泌或自分泌方式发挥作用。
