Anti-interleukin-6 receptor antibody treatment ameliorates postoperative adhesion formation
Anti-interleukin-6 receptor antibody treatment ameliorates postoperative adhesion formation
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DOI：
10.1038/s41598-019-54175-1
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发表时间：
2019-11-26
影响因子：
4.6
通讯作者：
Fujimoto, Jiro
中科院分区：
文献类型：
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作者：
Uyama, Naoki;Tsutsui, Hiroko;Fujimoto, Jiro
术后粘连的形成往往会破坏生活质量或成为癌症等治愈性手术疾病的障碍。以前我们证明干扰素-γ促进纤维蛋白沉积驱动术后粘连形成。然而，其潜在的细胞和分子机制仍然知之甚少。我们发现，粘附的肌成纤维细胞主要表达浆膜层间皮细胞的标志分子。微阵列分析显示IL-6是一个关键的潜在参与者，这一点得到了剖腹手术后人类受试者腹腔液中IL-6水平升高的支持。盲肠烧灼小鼠的受损浆膜也表现出IL 6的诱导，随后是TNF，伴随着中性粒细胞的快速积累，其中大量表达TGF-β 1，纤维化的主要调节因子。除此之外，嗜中性粒细胞消融的小鼠显示出对粘附的诱导减少，这表明TGF-β 1（+）中性粒细胞触发了粘附。人嗜中性粒细胞对TNF-α和IL-6的应答分别表达TGFB 1和TNF。此外，抗IL-6受体单克隆抗体废除中性粒细胞募集和粘附形成。因此，IL-6信号转导代表了预防术后粘连的潜在靶点。
Postoperative adhesion formation often ruins the quality of life or is an obstacle to illnesses with curative operation such as cancer. Previously we demonstrated that interferon-gamma-promoted fibrin deposition drove postoperative adhesion formation. However, its underlying cellular and molecular mechanisms remain poorly understood. We found that myofibroblasts of the adhesion predominantly expressed signature molecules of mesothelial cells that line the serosa. Microarray analysis revealed IL-6 as a key underlying player, supported by elevated IL-6 levels in the peritoneal fluid of postlaparotomy human subjects. Injured serosa of cecum-cauterized mice also exhibited induction of Il6, which was followed by Tnf, concomitant with rapid accumulation of neutrophils, substantial population of which expressed TGF-beta 1, a master regulator of fibrosis. Besides, neutrophil-ablated mice showed reduction in induction of the adhesion, suggesting that TGF-beta 1(+)neutrophils triggered the adhesion. Human neutrophils expressed TGFB1 in response to TNF-alpha and TNF in response to IL-6. Moreover, anti-IL-6 receptor monoclonal antibody abrogated neutrophil recruitment and adhesion formation. Thus, IL-6 signaling represents a potential target for the prevention of postoperative adhesions.