Department of Immunology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
University of Oslo, Oslo, Norway.
Front Immunol. 2018 Sep 12;9:2035. doi: 10.3389/fimmu.2018.02035. eCollection 2018.
Elevated interleukin-6 (IL-6) and complement activation are associated with detrimental effects of inflammation in coronary artery disease (CAD). The complement anaphylatoxins C5a and C3a interact with their receptors; the highly inflammatory C5aR1, and the C5aR2 and C3aR. We evaluated the effect of the IL-6 receptor (IL-6R)-antagonist tocilizumab on the expression of the anaphylatoxin receptors in whole blood from non-ST-elevation myocardial infarction (NSTEMI) patients. Separately, anaphylatoxin receptor expression in peripheral blood mononuclear cells (PBMC) from patients with different entities of CAD was investigated. NSTEMI patients were randomized to one dose of tocilizumab ( = 28) or placebo ( = 32) and observed for 6 months. Whole blood samples drawn at inclusion, at day 2, 3 and after 6 months were used for mRNA isolation. Plasma was prepared for analysis of complement activation measured as sC5b-9 by ELISA. Furthermore, patients with different CAD entities comprising stable angina pectoris (SAP, = 22), non-ST-elevation acute coronary syndrome (NSTE-ACS, = 21) and ST-elevation myocardial infarction (STEMI, = 20) were included. PBMC was isolated from blood samples obtained at admission to hospital and mRNA isolated. Anaphylatoxin-receptor-expression was analyzed with qPCR using mRNA from whole blood and PBMC, respectively. Our main findings were (i) Tocilizumab decreased C5aR1 and C5aR2 mRNA expression significantly ( < 0.001) and substantially (>50%) at day 2 and 3, whereas C3aR expression was unaffected. (ii) Tocilizumab did not affect complement activation. (iii) In analyzes of different CAD entities, C5aR1 expression was significantly increased in all CAD subgroups compared to controls with the highest level in the STEMI patients ( < 0.001). For C5aR2 and C3aR the expression compared to controls were more moderate with increased expression of C5aR2 in the STEMI group ( < 0.05) and C3aR in the NSTE-ACS group ( < 0.05). Expression of C5aR1 and C5aR2 in whole blood was significantly attenuated by IL-6R-inhibition in NSTEMI patients. These receptors were significantly upregulated in PBMC CAD patients with particularly high levels of C5aR1 in STEMI patients.
白细胞介素 6（IL-6）和补体激活水平升高与冠状动脉疾病（CAD）炎症的不良影响有关。补体过敏毒素 C5a 和 C3a 与它们的受体相互作用；高炎症性 C5aR1、C5aR2 和 C3aR。我们评估了白细胞介素 6 受体（IL-6R）拮抗剂托珠单抗对非 ST 段抬高型心肌梗死（NSTEMI）患者全血中过敏毒素受体表达的影响。另外，还研究了不同 CAD 患者外周血单个核细胞（PBMC）中过敏毒素受体的表达。NSTEMI 患者随机分为托珠单抗（n=28）或安慰剂（n=32）组，观察 6 个月。在纳入时、第 2 天、第 3 天和 6 个月时采集全血样本，用于提取 mRNA。血浆用于通过 ELISA 测定 sC5b-9 分析补体激活。此外，还纳入了不同 CAD 实体的患者，包括稳定性心绞痛（SAP，n=22）、非 ST 段抬高型急性冠脉综合征（NSTE-ACS，n=21）和 ST 段抬高型心肌梗死（STEMI，n=20）。在入院时采集血液样本并分离 PBMC，提取 mRNA。使用全血和 PBMC 的 mRNA 通过 qPCR 分析过敏毒素受体表达。我们的主要发现是：（i）托珠单抗在第 2 天和第 3 天显著（<0.001）和大量（>50%）降低 C5aR1 和 C5aR2 mRNA 表达，而 C3aR 表达不受影响。（ii）托珠单抗不影响补体激活。（iii）在不同 CAD 实体的分析中，与对照组相比，所有 CAD 亚组的 C5aR1 表达均显著升高，STEMI 患者的水平最高（<0.001）。与对照组相比，C5aR2 和 C3aR 的表达更为适中，STEMI 组 C5aR2（<0.05）和 NSTE-ACS 组 C3aR（<0.05）表达增加。NSTEMI 患者中，白细胞介素 6R 抑制显著减弱了 C5aR1 和 C5aR2 在全血中的表达。这些受体在 CAD 患者的 PBMC 中显著上调，特别是 STEMI 患者的 C5aR1 水平很高。
