白细胞介素-2新的功能位点及其中枢镇痛作用

ANALGESIC DOMAIN OF INTERLEUKIN-2 AND ITS CENTRAL ANALGESIC EFFECT

白细胞介素－２（ＩＬ－２）不仅是重要的免疫调节因子，而且还具有重要的中枢调节作用。本实验以钾离子透入引起大鼠甩尾反应为指标，发现侧脑室注射ＩＬ—２能显著提高动物痛阈，并能被纳洛酮所阻断，表示ＩＬ－２的中枢镇痛作用可能与阿片受体有关。利用基因定位突变技术获得的无免疫活性ＩＬ－２实查体仍具有中枢镇痛作用，表明ＩＬ—２分子上发挥镇痛和免疫调节作用的功能位点是相互独立的。纳洛酮能够阻断ＩＬ—２的中枢镇痛作用，而不能影响ＩＬ—２增殖ＣＴＬＬ－２细胞的作用，提示ＩＬ－２发挥镇痛和免疫调节作用可能通过不同的受体途径。ＩＬ－２分子中第４５位Ｔｙｒ残基突变为Ｖａｌ后，虽仍保留了免疫活性，但丧失了镇痛功能，表示４５位Ｔｙｒ残基是ＩＬ—２发挥中枢镇痛功能的关键残基之一。我们推测ＩＬ—２的镇痛功能位点可能在ＩＬ—２分子中第４５位Ｔｙｒ残基附近区域。

Interleukin-2 (IL-2) not only possess immunoregulatory activity, but also has important effect on central nervous system. We now report that IL-2 is an analgesic substance after injecting IL-2 into the lateral cerebral ventricle of rats. The pain threshold (PT) was evaluated by the tail-fiick induced by potassium iontophoresis. Naloxone could block the analgesic capability of IL-2, suggesting that analgesic effect of IL-2 be related to opiate receptors. The IL-2 mutant, which was obtained by oligonucleotide-mediated site-directed mutagenesis and had no immune activity, still had the analgesic capability, suggesting that there be different domains of immune and analgesic activity in IL-2 molecule. Since naloxone could block the analgesic effect, but not the proliferating effect on CTLL-2 cells of IL-2,it is suggested that the immune and analgesic effect of IL-2 might be mediated by different receptors. There was no analgesic effect after the 45th residue (Tyr) of IL-2 molecule was mutated to Val, despite that 45Val-IL-2 still had immune activity, suggesting that the 45th residue-Tyr be one of the crucial residues of IL-2 for its analgesic effect. It is suggested that the analgesic functional site(s) of IL-2 may be located at the domain around the 45th Tyr-residue of IL-2 molecule.