Scalavino Viviana, Piccinno Emanuele, Giannelli Gianluigi, Serino Grazia
National Institute of Gastroenterology S. De Bellis, IRCCS Research Hospital, Via Turi 27, Castellana Grotte, 70013 Bari, Italy.
Int J Mol Sci. 2025 May 1;26(9):4288. doi: 10.3390/ijms26094288.
Inflammatory Bowel Disease (IBD) is a group of chronic and recurrent inflammatory diseases characterized by prolonged inflammation of the intestinal tract. Although it has been proven that the immune system plays a crucial role in the pathogenesis of IBD, a defective intestinal epithelium is also responsible for chronic inflammation, hence causing an over-activation of the immune response. For this reason, a therapeutic approach that acts by improving impaired intestinal homeostasis could ensure a greater therapeutic efficacy in IBD. Mitogen-activated protein kinases (MAPKs) signaling pathways may be involved in the pathogenesis of IBD. It has been demonstrated that the inhibition of mitogen-activated protein kinase kinase 1 (MEK1) may be a potential treatment against IBD since it may restore the normal epithelial function and reduce apoptosis of intestinal epithelial cells (IECs). New therapeutic strategies are emerging including small molecules such as microRNAs (miRNAs). In this study, we aimed to demonstrate that miR-369-3p was able to modulate the MEK/ERK signaling pathway. As reported by in silico analysis, miR-369-3p was capable of pairing the 3'UTR of the MAP2K1 gene. In vitro analysis demonstrated that mimic transfection with miR-369-3p in epithelial cells downregulated the expression of MEK1, reduced the activation of ERK signaling, and modulated apoptosis of epithelial cells in response to TNF-α. Moreover, miR-369-3p significantly decreased the release of pro-inflammatory cytokine IL-8. These results support the potential of miR-369-3p to prevent apoptosis of IECs, responsible for a persistent inflammatory condition in IBD, highlighting its application value in the treatment of inflammatory disorders.
炎症性肠病（IBD）是一组慢性复发性炎症性疾病，其特征是肠道长期炎症。尽管已经证明免疫系统在IBD的发病机制中起关键作用，但肠道上皮细胞缺陷也会导致慢性炎症，从而引起免疫反应过度激活。因此，一种通过改善受损肠道内环境稳定起作用的治疗方法可能会确保在IBD中具有更高的治疗效果。丝裂原活化蛋白激酶（MAPK）信号通路可能参与IBD的发病机制。已经证明，抑制丝裂原活化蛋白激酶激酶1（MEK1）可能是一种针对IBD的潜在治疗方法，因为它可能恢复正常的上皮功能并减少肠道上皮细胞（IEC）的凋亡。新的治疗策略正在出现，包括小分子如微小RNA（miRNA）。在本研究中，我们旨在证明miR-369-3p能够调节MEK/ERK信号通路。如通过计算机分析所报道的，miR-369-3p能够与MAP2K1基因的3'UTR配对。体外分析表明，在上皮细胞中用miR-369-3p进行模拟转染可下调MEK1的表达，降低ERK信号的激活，并调节上皮细胞对TNF-α的凋亡反应。此外，miR-369-3p显著降低促炎细胞因子IL-8的释放。这些结果支持miR-369-3p预防IEC凋亡的潜力，IEC凋亡是IBD中持续性炎症状态的原因，突出了其在炎症性疾病治疗中的应用价值。
