THE ROLE OF LOW-AFFINITY INTERLEUKIN-2 RECEPTORS IN AUTOCRINE LIGAND-BINDING - ALTERNATIVE MECHANISMS FOR ENHANCED BINDING EFFECT
THE ROLE OF LOW-AFFINITY INTERLEUKIN-2 RECEPTORS IN AUTOCRINE LIGAND-BINDING - ALTERNATIVE MECHANISMS FOR ENHANCED BINDING EFFECT
复制标题
DOI：
10.1016/0161-5890(94)90148-1
复制
发表时间：
1994-07-01
影响因子：
3.6
通讯作者：
LAUFFENBURGER, DA
中科院分区：
文献类型：
--
作者：
FORSTEN, KE;LAUFFENBURGER, DA
t细胞增殖受自分泌配体白介素-2 （IL-2）调节，这些细胞具有双重、低亲和力和高亲和力受体群体。IL-2刺激的增殖依赖于配体与p75的结合，p75是高亲和力受体的一个组成部分。因此，与其他表现出双受体系统的细胞一样，一个核心问题是：低亲和受体群体的作用是什么？我们应用数学建模的方法来检查已经提出的低亲和力受体的作用的三种替代机制：配体库，受体库和配体载体。使用特定于IL-2/ t细胞系统的模型参数值，我们发现只有配体载体机制导致自分泌配体与高亲和力受体的结合，其水平高于单个预形成的高亲和力受体群体。在配体储库和受体储库机制下，由于竞争，低亲和力受体的存在实际上减少了高亲和力受体的结合。相反，当包括膜运输时，过量的低亲和受体可以增强高亲和受体复合物的水平，这表明如果这种机制被抑制，细胞反应可能会减少或消除。配体载体效应对于表达大量（bbb10(5)受体/细胞）低亲和受体和低细胞密度(
T-cell proliferation is regulated by the autocrine ligand interleukin-2 (IL-2), for which these cells possess dual, low-affinity and high-affinity receptor populations. Proliferation stimulated by IL-2 is dependent upon ligand binding to p75, a component of the high-affinity receptor. As with other cells exhibiting dual receptor systems, a central question is, therefore: what is the role of the low-affinity receptor population? We apply a mathematical modeling approach to examine three alternative mechanisms that have been suggested for the role of low-affinity receptors: a ligand reservoir, a receptor reservoir, and a ligand carrier. Using model parameter values specific to the IL-2/T-cell system, we find that only the ligand carrier mechanism leads to binding of autocrine ligand to high-affinity receptors that is increased over levels found on a single, pre-formed high-affinity receptor population. With the ligand reservoir and the receptor reservoir mechanisms, the presence of the low-affinity receptors actually diminishes high-affinity receptor binding due to competition. In contrast, excess low-affnity receptors can act to enhance the level of high-affinity receptor complexes when membrane transport is included, indicating that should this mechanism be inhibited, cell response could potentially be reduced or eliminated. The ligand carrier effect is especially significant for cells expressing a large number (>10(5) receptors/cell) low-affinity receptors, and at low cell densities (