Mucosal Inflammation Program, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA.
Mucosal Immunol. 2013 Nov;6(6):1110-8. doi: 10.1038/mi.2013.6. Epub 2013 Mar 6.
Antimicrobial peptides are secreted by the intestinal epithelium to defend from microbial threats. The role of human β defensin-1 (hBD-1) is notable because its gene (beta-defensin 1 (DEFB1)) is constitutively expressed and its antimicrobial activity is potentiated in the low-oxygen environment that characterizes the intestinal mucosa. Hypoxia-inducible factor (HIF) is stabilized even in healthy intestinal mucosa, and we identified that epithelial HIF-1α maintains expression of murine defensins. Extension to a human model revealed that basal HIF-1α is critical for the constitutive expression of hBD-1. Chromatin immunoprecipitation identified HIF-1α binding to a hypoxia response element in the DEFB1 promoter whose importance was confirmed by site-directed mutagenesis. We used 94 human intestinal samples to identify a strong expression correlation between DEFB1 and the canonical HIF-1α target GLUT1. These findings indicate that basal HIF-1α is critical for constitutive expression of enteric DEFB1 and support targeting epithelial HIF for restoration and maintenance of intestinal integrity.
抗菌肽由肠道上皮细胞分泌，以抵御微生物的威胁。人β防御素-1（hBD-1）的作用非常显著，因为它的基因（β防御素 1（DEFB1））是组成型表达的，其抗菌活性在肠道黏膜特有的低氧环境中得到增强。缺氧诱导因子（HIF）在健康的肠道黏膜中也能稳定存在，我们发现上皮细胞 HIF-1α 维持着鼠类防御素的表达。扩展到人类模型中发现，基础 HIF-1α 对 hBD-1 的组成型表达至关重要。染色质免疫沉淀法确定了 HIF-1α 与 DEFB1 启动子中的缺氧反应元件结合，通过定点突变证实了其重要性。我们使用 94 个人类肠道样本，鉴定出 DEFB1 与经典的 HIF-1α 靶标 GLUT1 之间存在强烈的表达相关性。这些发现表明，基础 HIF-1α 对肠道 DEFB1 的组成型表达至关重要，并支持针对上皮细胞 HIF 的靶向治疗，以恢复和维持肠道完整性。
