Transgenic interleukin 11 expression causes cross-tissue fibro-inflammation and an inflammatory bowel phenotype in mice
Transgenic interleukin 11 expression causes cross-tissue fibro-inflammation and an inflammatory bowel phenotype in mice
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DOI：
10.1371/journal.pone.0227505
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发表时间：
2020-01-09
期刊：
影响因子：
3.7
通讯作者：
Schafer, Sebastian
中科院分区：
文献类型：
--
作者：
Lim, Wei-Wen;Ng, Benjamin;Schafer, Sebastian
白细胞介素11（IL 11）是一种促纤维化细胞因子，由肌成纤维细胞和受损的上皮细胞分泌。平滑肌细胞（SMC）在病理条件下也分泌IL 11并表达IL 11受体。在这里，我们研究了SMC特异性，鼠IL 11的条件表达在转基因小鼠（IL 11（SMC））的影响。在转基因激活的几天内，IL 11（SMC）小鼠出现稀便、进行性出血和直肠脱垂，这与两周内65%的死亡率相关。IL 11（SMC）小鼠的肠发炎、纤维化并且具有增厚的壁，这伴随着ERK和STAT3的激活。在其他器官中，包括心、肺、肝、肾和皮肤，存在纤维炎症的表型谱，以及一致的ERK激活。为了进一步研究基质来源的IL 11在炎症性肠表型中的重要性，我们使用了具有成纤维细胞特异性表达IL 11的第二种模型，即IL 11（Fib）小鼠。这种额外的模型在很大程度上表型模仿了IL 11（SMC）肠表型。这些数据表明，从间质小生境分泌的IL11足以驱动小鼠的炎症性肠病。鉴于IL 11在结肠基质细胞中的表达预测溃疡性结肠炎或克罗恩病患者抗TNF治疗失败，我们建议IL 11作为炎症性肠病的治疗靶点。
Interleukin 11 (IL11) is a profibrotic cytokine, secreted by myofibroblasts and damaged epithelial cells. Smooth muscle cells (SMCs) also secrete IL11 under pathological conditions and express the IL11 receptor. Here we examined the effects of SMC-specific, conditional expression of murine IL11 in a transgenic mouse (Il11(SMC)). Within days of transgene activation, Il11(SMC) mice developed loose stools and progressive bleeding and rectal prolapse, which was associated with a 65% mortality by two weeks. The bowel of Il11(SMC) mice was inflamed, fibrotic and had a thickened wall, which was accompanied by activation of ERK and STAT3. In other organs, including the heart, lung, liver, kidney and skin there was a phenotypic spectrum of fibro-inflammation, together with consistent ERK activation. To investigate further the importance of stromal-derived IL11 in the inflammatory bowel phenotype we used a second model with fibroblast-specific expression of IL11, the Il11(Fib) mouse. This additional model largely phenocopied the Il11(SMC) bowel phenotype. These data show that IL11 secretion from the stromal niche is sufficient to drive inflammatory bowel disease in mice. Given that IL11 expression in colonic stromal cells predicts anti-TNF therapy failure in patients with ulcerative colitis or Crohn's disease, we suggest IL11 as a therapeutic target for inflammatory bowel disease.