Ji Tuo, Takabayashi Hidehiko, Mao Maria, Han Xu, Xue Xiang, Brazil Jennifer C, Eaton Kathryn A, Shah Yatrik M, Todisco Andrea
Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan.
Department of Molecular and Integrative Physiology, University of Michigan Medical Center, Ann Arbor, Michigan.
Am J Physiol Gastrointest Liver Physiol. 2017 Jan 1;312(1):G24-G33. doi: 10.1152/ajpgi.00169.2016. Epub 2016 Nov 17.
The bone morphogenetic proteins (BMPs) regulate gastrointestinal homeostasis. We investigated the expression of BMP-4 and the localization and function of BMP signaling during colonic injury and inflammation. Mice expressing the β-galactosidase (β-gal) gene under the control of a BMP-responsive element (BRE), BMP-4-β-gal/ mice, and animals generated by crossing villin-Cre mice to mice with floxed alleles of BMP receptor 1A (villin-Cre;Bmpr1a) were treated with dextran sodium sulfate (DSS) to induce colonic injury and inflammation. Expression of BMP-4, β-gal, BMPR1A, IL-8, α-smooth muscle actin, and phosphorylated Smad1, -5, and -8 was assessed by X-Gal staining, quantitative RT-PCR, and immunohistochemistry. Morphology of the colonic mucosa was examined by staining with hematoxylin and eosin. The effect of IFN-γ, TNF-α, IL-1β, and IL-6 on BMP-4 mRNA expression was investigated in human intestinal fibroblasts, whereas that of BMP-4 on IL-8 was assessed in human colonic organoids. BMP-4 was localized in α-smooth muscle actin-positive mesenchymal cells while the majority of BMP-generated signals targeted the epithelium. DSS caused injury and inflammation leading to reduced expression of BMP-4 and of BMPR1A mRNAs, and to decreased BMP signaling. Deletion of BMPR1A enhanced colonic inflammation and damage. Administration of anti-TNF-α antibodies to DSS-treated mice ameliorated colonic inflammation and increased the expression of BMP-4 and BMPR1A mRNAs. TNF-α and IL-1β inhibited both basal and IFN-γ-stimulated BMP-4 expression, whereas IL-6 had no effect. BMP-4 reduced TNF-α-stimulated IL-8 mRNA expressor IL-8 mRNA expression in the organoids. Inflammation and injury inhibit BMP-4 expression and signaling, leading to enhanced colonic damage and inflammation. These observations underscore the importance of BMP signaling in the regulation of intestinal inflammation and homeostasis.
NEW & NOTEWORTHY: In this study we report a series of novel observations that underscore the importance of bone morphogenetic protein (BMP) signaling in the regulation of colonic homeostasis during the development of injury and inflammation. In particular, we present evidence that BMP signaling mitigates the response of the colonic epithelium to injury and inflammation and that cytokines, such as TNF-α and IL-1β, inhibit the expression of BMP-4.
骨形态发生蛋白（BMPs）调节胃肠道稳态。我们研究了BMP-4的表达以及BMP信号在结肠损伤和炎症过程中的定位与功能。用葡聚糖硫酸钠（DSS）处理在BMP反应元件（BRE）控制下表达β-半乳糖苷酶（β-gal）基因的小鼠（BMP-4-β-gal/小鼠），以及通过将绒毛蛋白-Cre小鼠与BMP受体1A（Bmpr1a）的floxed等位基因小鼠杂交产生的动物，以诱导结肠损伤和炎症。通过X-Gal染色、定量RT-PCR和免疫组织化学评估BMP-4、β-gal、BMPR1A、IL-8、α-平滑肌肌动蛋白以及磷酸化的Smad1、Smad5和Smad8的表达。用苏木精和伊红染色检查结肠黏膜的形态。在人肠道成纤维细胞中研究了IFN-γ、TNF-α、IL-1β和IL-6对BMP-4 mRNA表达的影响，而在人结肠类器官中评估了BMP-4对IL-8的影响。BMP-4定位于α-平滑肌肌动蛋白阳性的间充质细胞中，而大多数BMP产生的信号靶向上皮细胞。DSS导致损伤和炎症，导致BMP-4和BMPR1A mRNA表达降低，以及BMP信号传导减少。BMPR1A的缺失加剧了结肠炎症和损伤。给DSS处理的小鼠施用抗TNF-α抗体可改善结肠炎症，并增加BMP-4和BMPR1A mRNA的表达。TNF-α和IL-1β抑制基础和IFN-γ刺激的BMP-4表达，而IL-6没有影响。BMP-4降低了类器官中TNF-α刺激的IL-8 mRNA表达。炎症和损伤抑制BMP-4表达和信号传导，导致结肠损伤和炎症加剧。这些观察结果强调了BMP信号在调节肠道炎症和稳态中的重要性。
在本研究中，我们报告了一系列新的观察结果，强调了骨形态发生蛋白（BMP）信号在损伤和炎症发展过程中调节结肠稳态的重要性。特别是，我们提供的证据表明，BMP信号减轻了结肠上皮对损伤和炎症的反应，并且细胞因子，如TNF-α和IL-1β，抑制BMP-4的表达。
