Background & Aims

Although interactions between enteric glial cells (EGCs) and enteric mast cells have been demonstrated to play an important role in the pathogenesis of inflammatory bowel disease (IBD), the exact mechanisms by which EGCs regulate enteric mast cells are still unknown. The aims of this study were to investigate whether glial-derived neurotrophic factor (GDNF), which has been confirmed to be produced mostly by EGCs, might regulate enteric mast cells and ameliorate dextran sulfate sodium (DSS)-induced experimental colitis.

Methods

Recombinant adenoviral vectors encoding GDNF (Ad-GDNF) were administered intracolonically in experimental colitis induced by DSS. The disease activity index and histological score were measured. The expression of tumour necrosis factor-α (TNF-α), interleukin-6 and myeloperoxidase (MPO) activity were measured by ELISA assay. The expression of trypsin and β-hexosaminidase were evaluated. GDNF specific receptor (GFR-α1/RET) was detected. The calcium reflux was tested by microplate reader. The expression p-JNK was analyzed by western blot assay.

Results

GDNF resulted in a significant inhibition of the activation of enteric mast cells by down-regulating JNK signal pathway, lessening intracellular calcium influx, and then reducing the degranulation as well as the expression of pro-inflammatory cytokines via combing with its receptor (GFR-α1/RET) in mast cells, and these inhibitory effects were abrogated by treatment with neutralizing antibody against GDNF. Moreover, the administration of GDNF led to an amelioration of experimental colitis.

Conclusions

GDNF are able to regulate enteric mast cells and ameliorate experimental colitis. GDNF might be an important mediator of the cross-talk between EGCs and enteric mast cells, and GDNF might be a useful therapeutic drug for IBD.

中文翻译：

---

胶质细胞衍生的神经营养因子调节肠肥大细胞并改善硫酸葡聚糖钠诱导的实验性结肠炎。

背景与目标

尽管已证明肠神经胶质细胞（EGC）与肠肥大细胞之间的相互作用在炎症性肠病（IBD）的发病机理中起着重要作用，但EGC调节肠肥大细胞的确切机制仍是未知的。这项研究的目的是调查已被证实主要由EGC产生的神经胶质来源的神经营养因子（GDNF）是否可能调节肠肥大细胞并改善硫酸葡聚糖硫酸钠（DSS）诱导的实验性结肠炎。

方法

在DSS诱导的实验性结肠炎中，结肠内注射编码GDNF的重组腺病毒载体（Ad-GDNF）。测量疾病活动指数和组织学评分。ELISA法检测肿瘤坏死因子-α（TNF-α），白介素-6和髓过氧化物酶（MPO）的表达。评估胰蛋白酶和β-己糖胺酶的表达。检测到GDNF特异性受体（GFR-α1/ RET）。通过酶标仪检测钙的回流。通过蛋白质印迹分析法分析p-JNK的表达。

结果

GDNF通过下调JNK信号通路，减少细胞内钙内流，然后通过与其受体（GFR-α1结合）减少脱颗粒以及促炎性细胞因子的表达，显着抑制肠肥大细胞的活化。 / RET）在肥大细胞中，这些抑制作用通过用抗GDNF的中和抗体进行治疗而被取消。此外，GDNF的施用导致实验性结肠炎的改善。

结论

GDNF能够调节肠肥大细胞并改善实验性结肠炎。GDNF可能是EGC与肠肥大细胞之间串扰的重要介体，而GDNF可能是IBD的有用治疗药物。