The Epithelial Danger Signal IL-1α Is a Potent Activator of Fibroblasts and Reactivator of Intestinal Inflammation
The Epithelial Danger Signal IL-1α Is a Potent Activator of Fibroblasts and Reactivator of Intestinal Inflammation
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DOI：
10.1016/j.ajpath.2015.02.018
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发表时间：
2015-06-01
影响因子：
6
通讯作者：
Stylianou, Eleni
中科院分区：
文献类型：
--
作者：
Scarpa, Melania;Kessler, Sean;Stylianou, Eleni
肠上皮细胞（IEC）死亡是炎症性肠病（IBD）的典型症状。我们研究了：i) IEC 释放的坏死细胞产物（促炎介质）是否会加剧粘膜炎症，ii) HT29 细胞或人 IEC 的坏死细胞裂解物诱导人肠成纤维细胞 (HIF) 产生 IL-6 和 IL-8 的能力，以及 iii) 受损结肠细胞释放的 IL-1 α 是否会加剧实验性 IBD。坏死细胞裂解物有效诱导 HIF IL-6 和 IL-8 产生，不依赖于 Toll 样受体 2 和 4、晚期糖基化终产物受体、高迁移率族盒 1、尿酸、IL-33 或炎症小体激活。 IL-1 α 是 IEC 衍生的坏死细胞的关键产物，参与 HIF 细胞因子的产生。 IL-1α阳性细胞。在人类 IBD 和葡聚糖硫酸钠 (DSS) 诱导的结肠炎的上皮细胞中被鉴定。在结肠炎小鼠的粪便中先检测到 IL-1 α，然后再检测到 IL-1 β。在给予低剂量DSS后，IL-1α灌肠在DSS结肠炎恢复后重新激活炎症，诱导上皮下成纤维细胞中IL-1受体表达，甚至在没有明显结肠炎的小鼠中也激活从头炎症。 IL-1 α 通过诱导间充质细胞产生细胞因子来放大肠道炎症。 IL-1α介导的IEC成纤维细胞相互作用可能参与炎症的放大和持续，即使没有明显的肠道损伤。 IL-1α可能是治疗早期IBD或预防IBD再激活的靶点。
Intestinal epithelial cell (IEC) death is typical of inflammatory bowel disease (IBD). We investigated: i) whether IEC released necrotic cell products (proinflammatory mediators) amplify mucosal inflammation, ii) the capacity of necrotic cell lysates from HT29 cells or human IECs to induce human intestinal fibroblasts' (HIF) production of IL-6 and IL-8, and iii) whether IL-1 alpha, released by injured colonocytes, exacerbated experimental IBD. Necrotic cell lysates potently induced HIF IL-6 and IL-8 production independent of Toll-Like receptors 2 and 4, receptor for advanced glycation end-products, high-mobility group box 1, uric acid, IL-33, or inflammasome activation. IL-1 alpha was the key IEC-derived necrotic cell product involved in HIF cytokine production. IL-1 alpha positive cells. were identified in the epithelium in human IBD and dextran sulfate sodium (DSS)-induced colitis. IL-1 alpha was detected in the stool of colitic mice before IL-1 beta. IL-1 alpha enemas reactivated inflammation after DSS colitis recovery, induced IL-1 receptor expression in subepithelial fibroblasts, and activated de novo inflammation even in mice without overt colitis, after the administration of low-dose DSS. IL-1 alpha amplifies gut inflammation by inducing cytokine production by mesenchymal cells. IL-1 alpha mediated IEC fibroblast interaction may be involved in amplifying and perpetuating inflammation, even without obvious intestinal damage. IL-1 alpha may be a target for treating early IBD or preventing the reactivation of IBD.