Department of Gastroenterology, Shenzhen Longhua District Central Hospital, Shenzhen, Guangdong 518110, P.R. China.
Department of Gastroenterology, The Second People's Hospital of Shenzhen, Shenzhen, Guangdong 518035, P.R. China.
Mol Med Rep. 2018 Aug;18(2):2171-2181. doi: 10.3892/mmr.2018.9169. Epub 2018 Jun 14.
A growing body of evidence has demonstrated that Eph/ephrin signalling may serve a central role in intestinal diseases. However, whether erythropoietin‑producing hepatocellular (Eph)/ephrin signalling is associated with the development of post‑infectious irritable bowel syndrome (PI‑IBS) is still unknown. In the present study, the role of Eph/Ephrin signalling in lipopolysaccharide (LPS)‑induced intestinal injury was evaluated in vivo and in vitro. LPS treatment significantly increased the levels of proinflammatory mediators [monocyte chemoattractant protein‑1, tumour necrosis factor α, interleukin (IL)‑1β, IL‑6, intercellular adhesion molecule 1 and vascular cell adhesion molecule‑1], activated the EphA2‑Ephrin A1, protein kinase B (Akt)‑nuclear factor (NF)‑κB, Src‑NF‑κB and Wnt/β‑catenin signalling pathways, and inhibited EphB1‑Ephrin B3 signalling in colon tissues, and primary cultured enteric neuronal and glial cells. Notably, EphA2 monoclonal antibody (mAb) treatment or Ephrin B3 overexpression could partially alleviate the LPS‑induced upregulation of proinflammatory mediators, and Akt‑NF‑κB, Src‑NF‑κB and Wnt/β‑catenin signalling pathways. In addition, EphA2 mAb treatment could partially inhibit LPS‑induced inactivation of EphB‑Ephrin B3 signalling, while Ephrin B3 overexpression could abrogate LPS‑induced activation of EphA2‑Ephrin A1 signalling. EphB1/Ephrin B3 signalling may antagonise the EphA2/Ephrin A1‑dependent pathway following LPS treatment. The results associated with the EphA2 signaling pathway, indicated that Eph/ephrin signalling may serve a bidirectional role in LPS‑induced intestinal injury. Eph/ephrin signalling may be a novel therapeutic target for LPS‑induced intestinal injury and potentially PI‑IBS.
越来越多的证据表明 Eph/ephrin 信号可能在肠道疾病中发挥核心作用。然而，促红细胞生成素产生肝细胞（Eph）/ephrin 信号是否与感染后肠易激综合征（PI-IBS）的发展相关尚不清楚。在本研究中，评估了 Eph/Ephrin 信号在脂多糖（LPS）诱导的肠道损伤中的作用，包括体内和体外实验。LPS 处理显著增加了促炎介质的水平[单核细胞趋化蛋白-1、肿瘤坏死因子-α、白细胞介素（IL）-1β、IL-6、细胞间黏附分子 1 和血管细胞黏附分子 1]，激活了 EphA2-Ephrin A1、蛋白激酶 B（Akt）-核因子（NF）-κB、Src-NF-κB 和 Wnt/β-连环蛋白信号通路，并抑制了 EphB1-Ephrin B3 信号在结肠组织以及原代培养的肠神经元和神经胶质细胞中的信号。值得注意的是，EphA2 单克隆抗体（mAb）治疗或 Ephrin B3 过表达可部分缓解 LPS 诱导的促炎介质上调，以及 Akt-NF-κB、Src-NF-κB 和 Wnt/β-连环蛋白信号通路。此外，EphA2 mAb 治疗可部分抑制 LPS 诱导的 EphB-Ephrin B3 信号失活，而 Ephrin B3 过表达可消除 LPS 诱导的 EphA2-Ephrin A1 信号激活。EphB1-Ephrin B3 信号可能拮抗 LPS 处理后 EphA2-Ephrin A1 依赖性通路。与 EphA2 信号通路相关的结果表明，Eph/ephrin 信号可能在 LPS 诱导的肠道损伤中发挥双向作用。Eph/ephrin 信号可能是 LPS 诱导的肠道损伤和潜在的 PI-IBS 的新治疗靶点。
