Department of Nuclear Medicine, Seoul National University College of Medicine, South Korea; Tumor Biology Program, Seoul National University College of Medicine, South Korea; Cancer Research Institute, Seoul National University College of Medicine, South Korea.
Department of Nuclear Medicine, Seoul National University College of Medicine, South Korea; Cancer Research Institute, Seoul National University College of Medicine, South Korea; Tumor Microenvironment Global Core Research Center, Seoul National University, South Korea; Cancer Imaging Center, Seoul National University Hospital, South Korea.
Biochem Biophys Res Commun. 2018 Nov 17;506(1):216-222. doi: 10.1016/j.bbrc.2018.10.083. Epub 2018 Oct 19.
Rheumatoid arthritis (RA) is a chronic disease with systemic inflammation resulting in destruction of multiple articular cartilages and bones. Activated macrophage plays a pivotal role during the disease course and has been one of main targets to inhibit inflammatory reaction of RA by using biological disease-modifying anti-rheumatic drugs (bDMARDs). F-FEDAC is one of PET imaging agents targeting TSPO, which is overexpressed in activated macrophages. The aim of this study was to evaluate the roles of F-FEDAC PET as an in vivo imaging of activated macrophages on etanercept (ETN), a TNF-antagonist as one of bDMARDs in collagen induced arthritis mice. In RAW 264.7 cells, the expressions of TSPO as well as iNOS and infiltrated nucleus of NF-κB were induced by activation with lipopolysaccharide and interferon-gamma. TSPO expression was slightly attenuated by ETN treatment, not by methotrexate (MTX) as a cytotoxic agent. However, cell uptake of F-FEDAC did not show significant changes according to both of the treatments. Similarly in CIA mice, F-FEDAC uptake in inflamed paws on PET imaging did not show significant changes during both of the treatments, contrary to the uptake decrease of F-FDG, a glucose analog to reflect metabolic or active inflammatory activity. Interestingly, when we divided joints according to the degree of F-FEDAC uptake before ETN treatment, the joints of high F-FEDAC uptake showed better response to ETN than the joints with low F-FEDAC uptakes. In case of F-FDG, there was no such kinds of patterns. We can speculate that F-FEDAC PET imaging may identify activated macrophage-induced arthritis because that F-FEDAC can reflect activated macrophages, which is the therapeutic target of ETN by TNF antagonistic effect. Thus, in vivo imaging using F-FEDAC may be used as a predictor of therapeutic effects among those kinds of bDMARDs having anti-inflammatory actions to inhibit activated macrophage.
类风湿关节炎（RA）是一种慢性疾病，具有全身性炎症，导致多个关节软骨和骨骼破坏。活化的巨噬细胞在疾病过程中起着关键作用，并且一直是使用生物疾病修饰抗风湿药物（bDMARDs）抑制 RA 炎症反应的主要靶点之一。F-FEDAC 是一种针对 TSPO 的 PET 成像剂，TSPO 在活化的巨噬细胞中过度表达。本研究旨在评估 F-FEDAC PET 作为一种体内成像剂在胶原诱导性关节炎（CIA）小鼠中靶向 TNF 拮抗剂依那西普（ETN）作为 bDMARDs 之一的活化巨噬细胞的作用。在 RAW 264.7 细胞中，TSPO 的表达以及诱导型一氧化氮合酶（iNOS）和核因子-κB（NF-κB）的浸润核均通过脂多糖和干扰素-γ的激活而诱导。ETN 治疗轻微减弱了 TSPO 的表达，但对细胞毒性药物甲氨蝶呤（MTX）没有影响。然而，根据两种治疗方法，F-FEDAC 的细胞摄取并没有显示出显著变化。同样在 CIA 小鼠中，在 PET 成像中，炎症性爪子的 F-FEDAC 摄取在两种治疗方法中均未显示出显著变化，与葡萄糖类似物 F-FDG 的摄取减少相反，F-FDG 反映代谢或活性炎症活性。有趣的是，当我们根据 ETN 治疗前 F-FEDAC 摄取程度对关节进行分类时，F-FEDAC 摄取较高的关节对 ETN 的反应优于 F-FEDAC 摄取较低的关节。在 F-FDG 的情况下，没有这种模式。我们可以推测，F-FEDAC PET 成像可能识别由活化巨噬细胞引起的关节炎，因为 F-FEDAC 可以反映活化的巨噬细胞，而这是 ETN 通过 TNF 拮抗作用的治疗靶点。因此，使用 F-FEDAC 的体内成像可以用作具有抑制活化巨噬细胞的抗炎作用的 bDMARDs 中治疗效果的预测因子。
