Mucosal Inflammation Program, Department of Medicine, University of Colorado Denver, Aurora, CO 80045, USA.
J Immunol. 2011 Feb 1;186(3):1790-8. doi: 10.4049/jimmunol.1001442. Epub 2011 Jan 3.
Numerous studies have revealed that hypoxia and inflammation occur coincidentally in mucosal disorders, such as inflammatory bowel disease. During inflammation, epithelial-expressed hypoxia-inducible factor (HIF) serves an endogenously protective function. In this study, we sought to explore how mucosal immune responses influence HIF-dependent end points. Guided by a screen of relevant inflammatory mediators, we identified IFN-γ as a potent repressor of HIF-dependent transcription in human intestinal epithelial cells. Analysis of HIF levels revealed that HIF-1β, but not HIF-1α, is selectively repressed by IFN-γ in a JAK-dependent manner. Cloning and functional analysis of the HIF-1β promoter identified a prominent region for IFN-γ-dependent repression. Further studies revealed that colonic IFN-γ and HIF-1β levels were inversely correlated in a murine colitis model. Taken together, these studies demonstrated that intestinal epithelial HIF is attenuated by IFN-γ through transcriptional repression of HIF-1β. These observations are relevant to the pathophysiology of colitis (i.e., that loss of HIF signaling during active inflammation may exacerbate disease pathogenesis).
大量研究表明，缺氧和炎症在黏膜疾病（如炎症性肠病）中同时发生。在炎症过程中，上皮细胞表达的缺氧诱导因子 (HIF) 发挥内源性保护作用。在这项研究中，我们试图探讨黏膜免疫反应如何影响 HIF 依赖性终点。在相关炎症介质的筛选指导下，我们发现 IFN-γ 是人类肠道上皮细胞中 HIF 依赖性转录的有效抑制剂。对 HIF 水平的分析表明，IFN-γ 以 JAK 依赖性方式选择性抑制 HIF-1β，而不是 HIF-1α。对 HIF-1β 启动子的克隆和功能分析确定了一个 IFN-γ 依赖性抑制的突出区域。进一步的研究表明，在小鼠结肠炎模型中，结肠 IFN-γ 和 HIF-1β 水平呈负相关。总之，这些研究表明，肠道上皮细胞中的 HIF 通过 HIF-1β 的转录抑制被 IFN-γ 减弱。这些观察结果与结肠炎的病理生理学相关（即，在活跃炎症期间 HIF 信号的丧失可能会加重疾病的发病机制）。
