Department of Radiology, University of Arizona, Tucson, P.O. Box 245067 Tucson, AZ 85724-5067, USA.
Nucl Med Biol. 2011 Aug;38(6):795-805. doi: 10.1016/j.nucmedbio.2011.02.012. Epub 2011 Apr 21.
Interleukin (IL)-1 and IL-18 are potent proinflammatory cytokines in inflammation-related diseases. Their actions are regulated by IL-1 receptor antagonist (IL-1ra) and IL-18 binding protein (IL-18bp). This study was designed to (99m)Tc-radiolabel an IL-1ra and IL-18bp dual-domain cytokine ligand, IL-18bp-Fc-IL-1ra, for specific inflammation targeting.
The (99m)Tc-IL-18bp-Fc-IL-1ra was obtained by direct labeling via 2-iminothiolane reduction. Competitive binding of (99m)Tc-labeled and unlabeled IL-18bp-Fc-IL-1ra to rat polymorphonuclear leukocytes was assessed in vitro. A mouse ear edema model was used to evaluate specific targeting properties of (99m)Tc-IL-18bp-Fc-IL1ra in vivo. The correlation between (99m)Tc-IL-18bp-Fc-IL-1ra uptake and (111)In-labeled polymorphonuclear neutrophil infiltration was studied using ischemic-reperfused rat hearts.
Direct (99m)Tc-labeling yielded a stable dual-domain cytokine radioligand with radiochemical purity greater than 95% after gel filtration. Competitive binding studies showed specific targeting of (99m)Tc-IL-18bp-Fc-IL-1ra to inflammatory cells. The (99m)Tc-IL-18bp-Fc-IL-1ra uptake was 1.80±0.17 % injected dose per gram (%ID/g) in the inflamed ear without blocking, whereas uptake in the presence of IL-18bp-Fc-IL-1ra was 1.09±0.08 %ID/g (P<.05). The amounts of IL-1β and IL-18 were significantly increased in the inflamed ears compared to the vehicle controls. A significant correlation of (99m)Tc-IL-18bp-Fc-IL-1ra with (111)In-labeled neutrophil distribution was observed in the ischemic-reperfused hearts (P<.001).
Targeting proinflammatory cytokines with (99m)Tc-IL-18bp-Fc-IL-1ra may provide a suitable approach for specific detection of inflammatory sites.
白细胞介素（IL）-1 和 IL-18 是炎症相关疾病中强有力的促炎细胞因子。它们的作用受白细胞介素 1 受体拮抗剂（IL-1ra）和白细胞介素 18 结合蛋白（IL-18bp）的调节。本研究旨在设计一种（99m）Tc 放射性标记的 IL-18bp-Fc-IL-1ra 双重细胞因子配体，用于特异性炎症靶向。
通过 2-亚氨基硫醇烷还原直接标记（99m）Tc-IL-18bp-Fc-IL-1ra。在体外评估（99m）Tc 标记和未标记的 IL-18bp-Fc-IL-1ra 与大鼠多形核白细胞的竞争结合。使用小鼠耳水肿模型评估（99m）Tc-IL-18bp-Fc-IL1ra 在体内的特异性靶向特性。使用缺血再灌注大鼠心脏研究（99m）Tc-IL-18bp-Fc-IL-1ra 摄取与（111）In 标记的多形核中性粒细胞浸润之间的相关性。
直接（99m）Tc 标记得到了一种稳定的双域细胞因子放射性配体，凝胶过滤后放射化学纯度大于 95%。竞争结合研究表明，（99m）Tc-IL-18bp-Fc-IL-1ra 特异性靶向炎症细胞。在未阻断的情况下，炎症耳中的（99m）Tc-IL-18bp-Fc-IL-1ra 摄取为 1.80±0.17% 注射剂量/克（%ID/g），而在存在 IL-18bp-Fc-IL-1ra 的情况下为 1.09±0.08%ID/g（P<.05）。与载体对照组相比，炎症耳中的 IL-1β 和 IL-18 含量显著增加。在缺血再灌注心脏中观察到（99m）Tc-IL-18bp-Fc-IL-1ra 与（111）In 标记的中性粒细胞分布之间存在显著相关性（P<.001）。
用（99m）Tc-IL-18bp-Fc-IL-1ra 靶向促炎细胞因子可能为炎症部位的特异性检测提供一种合适的方法。
