Ma Y, Hurst H E, Fernandez-Botran R
Department of Microbiology and immunology, School of Medicine, University of Louisville, Kentucky, USA.
J Pharmacol Exp Ther. 1996 Oct;279(1):340-50.
Soluble interleukin-4 (IL-4) receptors (sIL-4R) can have either enhancing or inhibitory effects on the activity of IL-4 in vivo, depending on the relative concentration ratios of sIL-4R to IL-4. Whereas competition with membrane IL-4 receptors is the basis for their inhibitory action, the mechanisms responsible for the potentiation of IL-4 activity are not completely clear but may involve alterations in the half-life and biodistribution of IL-4 in vivo. To better understand the basis for the enhancing effect of sIL-4R, we have analyzed their effects on the pharmacokinetic properties of IL-4. Studies with radiolabeled recombinant IL-4 demonstrated that, when injected alone, IL-4 was rapidly cleared from the circulation and eliminated through the kidneys in a proteolytically degraded form. Administration of IL-4 in combination with increasing concentrations of sIL-4R resulted in a dose-dependent enhancement in the blood levels of IL-4 and a concomitant reduction in its clearance from circulation and excretion in the urine. Differences between measurements of IL-4 concentrations based on radioactivity and enzyme-linked immunosorbent assays indicated that the injected IL-4 was rapidly inactivated in vivo and that the presence of sIL-4R diminished this process. The inactivation of IL-4 was mediated through the membrane IL-4 receptors and required receptor internalization and intact lysosomal function. Taken together, these results suggest that sIL-4R are able to alter the pharmacokinetic properties of IL-4, prolonging its half-life in the circulation and reducing its clearance through diminished renal excretion and/or interference with inactivation. These effects are consistent with the ability of sIL-4R to potentiate IL-4 activity in vivo.
可溶性白细胞介素-4（IL-4）受体（sIL-4R）在体内对IL-4的活性可产生增强或抑制作用，这取决于sIL-4R与IL-4的相对浓度比。与膜IL-4受体竞争是其抑制作用的基础，而IL-4活性增强的机制尚不完全清楚，但可能涉及IL-4在体内半衰期和生物分布的改变。为了更好地理解sIL-4R增强作用的基础，我们分析了它们对IL-4药代动力学特性的影响。用放射性标记的重组IL-4进行的研究表明，单独注射时，IL-4迅速从循环中清除，并以蛋白水解降解的形式通过肾脏排出。将IL-4与浓度不断增加的sIL-4R联合给药，导致IL-4血药浓度呈剂量依赖性升高，同时其从循环中的清除率和尿排泄量降低。基于放射性和酶联免疫吸附测定的IL-4浓度测量结果之间的差异表明，注射的IL-4在体内迅速失活，而sIL-4R的存在减弱了这一过程。IL-4的失活是通过膜IL-4受体介导的，需要受体内化和完整的溶酶体功能。综上所述，这些结果表明sIL-4R能够改变IL-4的药代动力学特性，延长其在循环中的半衰期，并通过减少肾脏排泄和/或干扰失活来降低其清除率。这些效应与sIL-4R在体内增强IL-4活性的能力一致。
