TFF2 deficiency exacerbates weight loss and alters immune cell and cytokine profiles in DSS colitis, and this cannot be rescued by wild-type bone marrow
TFF2 deficiency exacerbates weight loss and alters immune cell and cytokine profiles in DSS colitis, and this cannot be rescued by wild-type bone marrow
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DOI：
10.1152/ajpgi.00172.2014
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发表时间：
2015-01-01
影响因子：
4.5
通讯作者：
Giraud, Andrew S.
中科院分区：
文献类型：
--
作者：
Judd, Louise M.;Chalinor, Heather V.;Giraud, Andrew S.
三叶因子TFF 2是由胃和结肠产生的小蛋白质的三方家族的成员。重组TFF 2，当应用于半抗原结肠炎的啮齿动物模型直肠内时，加速粘膜愈合并降低炎症指数。此外，TFF 2在免疫器官中表达，支持肠道中潜在的免疫调节和修复作用。在这项研究中，我们证实，TFF 2在结肠中表达，并特别是在上皮细胞相对于结肠白细胞富集。TFF 2缺陷，但不是TFF 1缺陷，小鼠表现出更严重的急性或慢性硫酸葡聚糖（DSS）诱导的结肠炎，与TFF 3，主要的结肠三叶表达的50%的损失。此外，对急性结肠炎的反应与IL-6和IL-33的表达改变有关，但与其他炎性细胞因子无关。虽然TFF 2可以降低巨噬细胞反应性并阻断炎症细胞向结肠的募集，但限制对急性结肠炎易感性的主要作用似乎是维持屏障功能。骨髓转移实验表明，TFF 2的白细胞表达不足以预防结肠炎诱导，而是胃肠道上皮细胞是TFF 2的主要来源。总之，这些发现说明上皮TFF 2是肠道粘膜稳态的重要内源性调节剂，可以调节免疫和上皮隔室。由于其极端的稳定性，即使在腐蚀性肠腔中，TFF 2也是一种有吸引力的候选物，可作为未来治疗炎症性肠病药物开发的口服治疗支架。
The trefoil factor TFF2 is a member of a tripartite family of small proteins that is produced by the stomach and the colon. Recombinant TFF2, when applied intrarectally in a rodent model of hapten colitis, hastens mucosal healing and reduces inflammatory indexes. Additionally, TFF2 is expressed in immune organs, supporting a potential immunomodulatory and reparative role in the bowel. In this study we confirm that TFF2 is expressed in the colon and is specifically enriched in epithelial cells relative to colonic leukocytes. TFF2-deficient, but not TFF1-deficient, mice exhibit a more severe response to acute or chronic dextran sulfate (DSS)-induced colitis that correlates with a 50% loss of expression of TFF3, the principal colonic trefoil. In addition, the response to acute colitis is associated with altered expression of IL-6 and IL-33, but not other inflammatory cytokines. While TFF2 can reduce macrophage responsiveness and block inflammatory cell recruitment to the colon, the major role in limiting the susceptibility to acute colitis appears to be maintenance of barrier function. Bone marrow transfer experiments demonstrate that leukocyte expression of TFF2 is not sufficient for prevention of colitis induction but, rather, that the gastrointestinal epithelium is the primary source of TFF2. Together, these findings illustrate that epithelial TFF2 is an important endogenous regulator of gut mucosal homeostasis that can modulate immune and epithelial compartments. Because of its extreme stability, even in the corrosive gut lumen, TFF2 is an attractive candidate as an oral therapeutic scaffold for future drug development in the treatment of inflammatory bowel disease.