Interferon Gamma Counteracts the Angiogenic Switch and Induces Vascular Permeability in Dextran Sulfate Sodium Colitis in Mice
Interferon Gamma Counteracts the Angiogenic Switch and Induces Vascular Permeability in Dextran Sulfate Sodium Colitis in Mice
复制标题
γ干扰素抵消小鼠右旋糖酐硫酸钠结肠炎的血管生成开关并诱导血管通透性
DOI：
10.1097/mib.0000000000000490
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发表时间：
2015-10-01
影响因子：
4.9
通讯作者：
Stuerzl, Michael
中科院分区：
文献类型：
--
作者：
Haep, Lisa;Britzen-Laurent, Nathalie;Stuerzl, Michael
背景：干扰素（IFN）是炎症性肠病（IBD）的主要致病因子，对许多不同类型的细胞具有多效性作用。然而，迄今为止，IFN-γ在IBD中的免疫调节功能已被主要研究。根据以往的研究表明，IFN-α的行为抗血管生成的结直肠癌，我们调查了IFN-α对血管系统的影响，在IBD。方法：IBD和葡聚糖硫酸钠诱导的结肠炎小鼠患者的结肠组织进行免疫组化，定量实时聚合酶链反应，原位杂交，以量化细胞活化，血管生成和免疫反应。结果：IBD和葡聚糖硫酸钠结肠炎小鼠血管密度明显增加，血管通透性增加。在小鼠中，这与血管结构紊乱和严重的血管渗漏有关。与血管生成相关基因相比，炎症细胞激活相关基因（包括IFN-γ）在结肠炎组织中表达上调更强。IFN-γ对IBD组织中的内皮细胞产生直接影响，如IFN-γ诱导的鸟苷酸结合蛋白1（GBP-1）的表达所示。IFN-在急性葡聚糖硫酸钠结肠炎模型中的中和表明，这种细胞因子发挥内源性血管生长抑制活性在IBD和有助于增加血管permeability.Conclusions：IFN-在IBD多效性活动的解剖提供了新的见解，这种细胞因子的病理功能，并可能是高度相关的组合治疗方法的优化。
Background:Interferon (IFN)- is a central pathogenesis factor in inflammatory bowel disease (IBD) with pleiotropic effects on many different cell types. However, as yet, the immune modulatory functions of IFN- in IBD have been predominantly investigated. Based on previous studies showing that IFN- acts antiangiogenic in colorectal carcinoma, we investigated the effects of IFN- on the vascular system in IBD.Methods:Colon tissues of patients with IBD and dextran sulfate sodium-induced colitis in mice were subjected to immunohistochemistry, quantitative real-time polymerase chain reactions, and in situ hybridization to quantify cell activation, angiogenesis, and immune responses. Vascular structure and permeability in mice were analyzed by ultramicroscopy and in vivo confocal laser endomicroscopy.Results:We showed a significantly increased blood vessel density in IBD and dextran sulfate sodium colitis. In mice, this was associated with a disorganized blood vessel structure and profound vascular leakage. As compared with genes associated with angiogenesis, genes associated with inflammatory cell activation including IFN- were more strongly upregulated in colitis tissues. IFN- exerted direct effects on endothelial cells in IBD tissues in vivo, as indicated by the expression of IFN--induced guanylate binding protein 1 (GBP-1). Neutralization of IFN- in the acute dextran sulfate sodium colitis model demonstrated that this cytokine exerts endogenous angiostatic activity in IBD and contributes to increased vascular permeability.Conclusions:The dissection of the pleiotropic activities of IFN- in IBD provides new insights to the pathological functions of this cytokine and may be of high relevance for the optimization of combination therapy approaches.