Modulation of enteric neurons by interleukin-6 and corticotropin-releasing factor contributes to visceral hypersensitivity and altered colonic motility in a rat model of irritable bowel syndrome
Modulation of enteric neurons by interleukin-6 and corticotropin-releasing factor contributes to visceral hypersensitivity and altered colonic motility in a rat model of irritable bowel syndrome
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DOI：
10.1113/jphysiol.2014.279968
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发表时间：
2014-12-01
影响因子：
5.5
通讯作者：
O'Malley, Dervla
中科院分区：
文献类型：
--
作者：
Buckley, Maria M.;O'Halloran, Ken D.;O'Malley, Dervla
应激系统的过度活跃和低度免疫激活是功能性肠病肠易激综合征 (IBS) 的特征。这些研究表明，IBS 血浆中存在的白细胞介素 (IL)-6 和 IL-8 以及应激激素促肾上腺皮质激素释放因子 (CRF) 通过刺激肌间神经元和结肠对胃肠活动产生功能性影响 此外，在 Wistar京都大鼠 IBS 模型中，肠胃蠕动和内脏疼痛敏感性发生改变，阻断 IL-6 和/或 CRF1 受体可缓解这些 IBS 样症状。这些效应的根本原因是调节肠道屏障功能和 T 型钙通道 Ca(V)3.2 的紧密连接蛋白的结肠蛋白表达改变，该蛋白与肠道屏障功能和 T 型钙通道 Ca(V)3.2 相关。 这些发现证明了肠神经系统和肠道生理学在肠道功能障碍中的重要性。摘要：对肠易激综合征（IBS）的潜在病理生理学的不完全了解阻碍了对肠易激综合征（IBS）有效治疗策略的探索。表明免疫激活的压力和血浆细胞因子谱的改变是该疾病的特征。研究人员研究了白细胞介素 6 (IL-6) 和促肾上腺皮质激素释放因子受体 (CRFR) 1 对 Wistar京都 (WKY) IBS 大鼠模型内脏疼痛和应激性排便的神经调节作用。 Sprague Dawley和WKY大鼠在联合或不联合CRFR1拮抗剂antalarmin（10mgkg(-1) i.p）的情况下给予抗IL-6受体抗体（xIL-6R，0.5mgkg(-1) i.p）。干预后，比较结直肠扩张的痛阈和压力引起的粪便排出量，并研究结肠粘膜蛋白表达的变化。 IBS 血浆对肌间神经丛的神经刺激作用是由 IL-6、IL-8 和 CRF 介导的。这些可溶性因子对肌间神经元兴奋性和结肠收缩性的刺激作用是相加的。此外，在 WKY IBS 大鼠模型中体内抑制 IL-6 和 CRF1 受体可使应激诱导的排便正常化 (P
Key pointsHyperactivity of the stress system and low-grade immune activation characterize the functional bowel disorder irritable bowel syndrome (IBS).These studies show that interleukin (IL)-6 and IL-8 and the stress hormone corticotropin-releasing factor (CRF), present in IBS plasma, have functional effects on gastrointestinal activity by stimulating myenteric neurons and colonic contractions.Moreover, in the Wistar Kyoto rat model of IBS, which exhibits altered gastrointestinal motility and visceral pain sensitivity, blocking IL-6 and/or CRF1 receptors alleviates these IBS-like symptoms.Underlying these effects are altered colonic protein expression of tight junction proteins which regulate gut barrier function and the T-type calcium channel Ca(V)3.2, which has been linked to visceral pain.These findings demonstrate the importance of the enteric nervous system and intestinal physiology in bowel dysfunction.AbstractThe search for effective therapeutic strategies for irritable bowel syndrome (IBS) is hampered by an incomplete understanding of its underlying pathophysiology. Stress and altered plasma cytokine profiles indicative of immune activation are characteristic of the disorder. The neuromodulatory effects of interleukin-6 (IL-6) and corticotropin-releasing factor receptor (CRFR) 1 in visceral pain and stress-induced defecation in the Wistar Kyoto (WKY) rat model of IBS were investigated. Sprague Dawley and WKY rats were administered anti-IL-6 receptor antibodies (xIL-6R, 0.5mgkg(-1) i.p) with or without the CRFR1 antagonist antalarmin (10mgkg(-1) i.p). Post-intervention, the pain threshold to colorectal distension and stress-induced faecal output were compared and changes in colonic mucosal protein expression were investigated. The neuro-stimulatory effects of IBS plasma on the myenteric plexus is mediated by IL-6, IL-8 and CRF. The stimulatory effects of these soluble factors on myenteric neuron excitability and colonic contractility were additive. Moreover, inhibition of IL-6 and CRF1 receptors in vivo in the WKY IBS rat model normalized stress-induced defecation (P