Pang Lokman, Huynh Jennifer, Alorro Mariah G, Li Xia, Ernst Matthias, Chand Ashwini L
Olivia Newton-John Cancer Research Institute, La Trobe University School of Cancer Medicine, Heidelberg, VIC 3084, Australia.
Department of Mathematics and Statistics, La Trobe University, Bundoora, VIC 3083, Australia.
Biomedicines. 2021 Feb 12;9(2):187. doi: 10.3390/biomedicines9020187.
The intestinal epithelium provides a barrier against commensal and pathogenic microorganisms. Barrier dysfunction promotes chronic inflammation, which can drive the pathogenesis of inflammatory bowel disease (IBD) and colorectal cancer (CRC). Although the Signal Transducer and Activator of Transcription-3 (STAT3) is overexpressed in both intestinal epithelial cells and immune cells in IBD patients, the role of the interleukin (IL)-6 family of cytokines through the shared IL-6ST/gp130 receptor and its associated STAT3 signalling in intestinal barrier integrity is unclear. We therefore investigated the role of STAT3 in retaining epithelial barrier integrity using dextran sulfate sodium (DSS)-induced colitis in two genetically modified mouse models, to either reduce STAT1/3 activation in response to IL-6 family cytokines with a truncated allele (GP130), or by inducing short hairpin-mediated knockdown of (shStat3). Here, we show that mice with reduced STAT3 activity are highly susceptible to DSS-induced colitis. Mechanistically, the IL-6/gp130/STAT3 signalling cascade orchestrates intestinal barrier function by modulating cytokine secretion and promoting epithelial integrity to maintain a defence against bacteria. Our study also identifies a crucial role of STAT3 in controlling intestinal permeability through tight junction proteins. Thus, therapeutically targeting the IL-6/gp130/STAT3 signalling axis to promote barrier function may serve as a treatment strategy for IBD patients.
肠道上皮为共生微生物和致病微生物提供了一道屏障。屏障功能障碍会促进慢性炎症，进而推动炎症性肠病（IBD）和结直肠癌（CRC）的发病机制。尽管信号转导子和转录激活子3（STAT3）在IBD患者的肠道上皮细胞和免疫细胞中均有过表达，但白细胞介素（IL）-6细胞因子家族通过共享的IL-6ST/gp130受体及其相关的STAT3信号传导在肠道屏障完整性中的作用尚不清楚。因此，我们在两种基因改造小鼠模型中利用葡聚糖硫酸钠（DSS）诱导的结肠炎来研究STAT3在维持上皮屏障完整性中的作用，一种模型是通过截断等位基因（GP130）来降低对IL-6细胞因子家族细胞因子的STAT1/3激活，另一种模型是通过诱导短发夹介导的Stat3基因敲低（shStat3）。在此，我们表明STAT3活性降低的小鼠对DSS诱导的结肠炎高度敏感。从机制上讲，IL-6/gp130/STAT3信号级联通过调节细胞因子分泌和促进上皮完整性来协调肠道屏障功能，以维持对细菌的防御。我们的研究还确定了STAT3在通过紧密连接蛋白控制肠道通透性方面的关键作用。因此，通过治疗靶向IL-6/gp130/STAT3信号轴来促进屏障功能可能成为IBD患者的一种治疗策略。
