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首页> 外文期刊>PLoS Biology >The colonic epithelium plays an active role in promoting colitis by shaping the tissue cytokine profile
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The colonic epithelium plays an active role in promoting colitis by shaping the tissue cytokine profile

机译：结肠上皮通过塑造组织细胞因子剖面，在促进结肠炎方面发挥着积极作用

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Inflammatory bowel disease (IBD) is a chronic condition driven by loss of homeostasis between the mucosal immune system, the commensal gut microbiota, and the intestinal epithelium. Our goal is to understand how these components of the intestinal ecosystem cooperate to control homeostasis. By combining quantitative measures of epithelial hyperplasia and immune infiltration with multivariate analysis of inter- and intracellular signaling, we identified epithelial mammalian target of rapamycin (mTOR) signaling as a potential driver of inflammation in a mouse model of colitis. A kinetic analysis of mTOR inhibition revealed that the pathway regulates epithelial differentiation, which in turn controls the cytokine milieu of the colon. Consistent with our in vivo analysis, we found that cytokine expression of organoids grown ex vivo, in the absence of bacteria and immune cells, was dependent on differentiation state. Our study suggests that proper differentiation of epithelial cells is an important feature of colonic homeostasis because of its effect on the secretion of inflammatory cytokines. Author summary Chronic inflammation of the gastrointestinal track is the common defect shared by inflammatory bowel diseases (IBDs), such as Crohn’s disease and ulcerative colitis, which affect many people around the world. However, the genetic and physiologic complexities of IBDs have made it difficult to identify therapeutically tractable drivers of disease that can alleviate the symptoms. We reasoned that this complexity is probably originated by a smaller number of dysregulated signaling pathways, and therefore, a “protein-centric” approach would be more suited to identify new therapeutic targets. To this end, in this study we profiled the expression and phosphorylation status of proteins that mediate signaling between and within cells in a mouse model of colitis. We found that hyperactivated mammalian target of rapamycin (mTOR) signaling interferes with the proper differentiation of epithelial cells, which promotes colitis by altering the epithelial inflammatory cytokine secretion in the colon.
机译：炎症性肠病（IBD）是粘膜免疫系统，共生肠道微生物和肠上皮的损失驱动的慢性病。我们的目标是了解肠道生态系统的这些组分如何合作控制稳态。通过将上皮增生和免疫渗透的定量测量与细胞间信号传导的多变量分析相结合，我们将雷帕霉素（MTOR）信号传导的上皮哺乳动物靶标鉴定为结肠炎小鼠模型中炎症的潜在驱动器。 MTOR抑制的动力学分析显示，途径调节上皮分化，这反过来控制结肠的细胞因子Milieu。与我们的体内分析一致，我们发现在没有细菌和免疫细胞的情况下，种植体种植体的细胞因子表达依赖于分化状态。我们的研究表明，上皮细胞的适当分化是结肠稳态的重要特征，因为它对炎性细胞因子的分泌作用。作者摘要胃肠道慢性炎症是炎症性肠病（IBD）共享的常见缺陷，例如克罗恩病和溃疡性结肠炎，这影响了世界各地的许多人。然而，IBD的遗传和生理复杂性使得难以识别能够缓解症状的治疗疾病的治疗贸易驱动因素。我们推理，这种复杂性可能是较少数量的失调信号通路，因此，“以蛋白质为中心”的方法将更适合识别新的治疗目标。为此，在这项研究中，我们分解了蛋白质的表达和磷酸化状态，所述蛋白质在结肠炎小鼠模型中介导信号和细胞内的信号。我们发现雷帕霉素（MTOR）信号传导的多动哺乳动物靶引起上皮细胞的适当分化，通过改变结肠中的上皮炎症细胞因子分泌来促进结肠炎。

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