Murata K, Motomura Y, Tanaka T, Kanno S, Yano T, Onimaru M, Shimoyama A, Nishio H, Sakai Y, Oh-Hora M, Hara H, Fukase K, Takada H, Masuda S, Ohga S, Yamasaki S, Hara T
Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Division of Molecular Immunology, Research Center for Infectious Diseases, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
Clin Exp Immunol. 2017 Oct;190(1):54-67. doi: 10.1111/cei.13002. Epub 2017 Jul 21.
Calcineurin inhibitors (CNIs) have been used off-label for the treatment of refractory Kawasaki disease (KD). However, it remains unknown whether CNIs show protective effects against the development of coronary artery lesions in KD patients. To investigate the effects of CNIs on coronary arteries and the mechanisms of their actions on coronary arteritis in a mouse model of KD, we performed experiments with FK565, a ligand of nucleotide-binding oligomerization domain-containing protein 1 (NOD1) in wild-type, severe combined immunodeficiency (SCID), caspase-associated recruitment domain 9 (CARD9) and myeloid differentiation primary response gene 88 (MyD88) mice. We also performed in-vitro studies with vascular and monocytic cells and vascular tissues. A histopathological analysis showed that both cyclosporin A and tacrolimus exacerbated the NOD1-mediated coronary arteritis in a dose-dependent manner. Cyclosporin A induced the exacerbation of coronary arteritis in mice only in high doses, while tacrolimus exacerbated it within the therapeutic range in humans. Similar effects were obtained in SCID and CARD9 mice but not in MyD88 mice. CNIs enhanced the expression of adhesion molecules by endothelial cells and the cytokine secretion by monocytic cells in our KD model. These data indicated that both vascular and monocytic cells were involved in the exacerbation of coronary arteritis. Activation of MyD88-dependent inflammatory signals in both vascular cells and macrophages appears to contribute to their adverse effects. Particular attention should be paid to the development of coronary artery lesions when using CNIs to treat refractory KD.
钙调神经磷酸酶抑制剂（CNIs）已被用于难治性川崎病（KD）的治疗，但未获批准。然而，CNIs对KD患者冠状动脉病变的发展是否具有保护作用仍不清楚。为了研究CNIs对KD小鼠模型冠状动脉的影响及其对冠状动脉炎的作用机制，我们使用FK565进行了实验，FK565是野生型、严重联合免疫缺陷（SCID）、半胱天冬酶相关募集结构域9（CARD9）和髓样分化初级反应基因88（MyD88）小鼠中含核苷酸结合寡聚化结构域蛋白1（NOD1）的配体。我们还对血管和单核细胞以及血管组织进行了体外研究。组织病理学分析表明，环孢素A和他克莫司均以剂量依赖性方式加剧了NOD1介导的冠状动脉炎。环孢素A仅在高剂量时诱导小鼠冠状动脉炎加剧，而他克莫司在人类治疗范围内加剧了冠状动脉炎。在SCID和CARD9小鼠中获得了类似的效果，但在MyD88小鼠中未获得。在我们的KD模型中，CNIs增强了内皮细胞黏附分子的表达和单核细胞的细胞因子分泌。这些数据表明，血管和单核细胞均参与了冠状动脉炎的加剧。血管细胞和巨噬细胞中MyD88依赖性炎症信号的激活似乎导致了它们的不良反应。使用CNIs治疗难治性KD时，应特别关注冠状动脉病变的发展。
