Antrum Mucosal Protein-18 Peptide Targets Tight Junctions to Protect and Heal Barrier Structure and Function in Models of Inflammatory Bowel Disease.
Antrum Mucosal Protein-18 Peptide Targets Tight Junctions to Protect and Heal Barrier Structure and Function in Models of Inflammatory Bowel Disease.
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DOI：
10.1097/mib.0000000000000499
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发表时间：
2015-10
影响因子：
4.9
通讯作者：
Toback FG
中科院分区：
文献类型：
--
作者：
Chen P;Bakke D;Kolodziej L;Lodolce J;Weber CR;Boone DL;Toback FG
一种来源于胃窦粘膜蛋白(AMP)-18(胃动素-1)的多肽可减轻右旋糖苷硫酸钠(DSS)诱导的结肠损伤小鼠的粘膜侵蚀程度和临床严重程度。本研究旨在通过增强和稳定紧密连接(TJ)来确定AMP肽是否也对免疫和细胞因子介导的肠道损伤和炎症性肠病(IBD)小鼠模型具有治疗作用。采用免疫缺陷重组酶激活基因-1(RAG-1)基因敲除小鼠结肠炎模型和T细胞过继转移模型，观察AMP多肽对IL-10缺乏和T细胞过继转移的−/−小鼠的治疗作用。用脂多糖(LPS)染毒小鼠的肠道和结肠，以及给予DSS的AMP-18缺陷小鼠，在体外研究了AMP多肽增强屏障功能和结构的机制。在给予吡罗昔康的白介素10缺乏的小鼠中，AMP多肽促进了体重减轻后的恢复，防止了结肠缩短和节段性扩张，并降低了结肠炎活动评分。在T细胞转移模型中，用这种多肽治疗可以防止结肠缩短。在体内注射脂多糖诱导肠道损伤的小鼠中，AMP多肽通过靶向TJ蛋白和连接周围肌动蛋白来预防和逆转已建立的肠道高通透性。与杂合子小鼠或野生型小鼠相比，用DSS攻击的AMP-18缺陷小鼠的死亡率增加，结肠出现侵蚀，TJ中ZO-1的水平较低。结果表明，AMP-18/肽可能对胃肠道粘膜屏障的损伤具有保护作用，建议进一步开发AMP-18/肽作为治疗IBD的新药物。
A peptide derived from Antrum Mucosal Protein (AMP)-18 (gastrokine-1) reduces the extent of mucosal erosions and clinical severity in mice with dextran sulfate sodium (DSS)-induced colonic injury. The present study set out to determine if AMP peptide was also therapeutic for immune- and cytokine-mediated mouse models of intestinal injury and inflammatory bowel diseases (IBD) by enhancing and stabilizing tight junctions (TJs). Therapeutic effects of AMP peptide were examined in interleukin-10 deficient and a T cell adoptive transfer models of colitis in immunodeficient recombinase activating gene-1 knock-out (RAG-1−/−) mice. Mechanisms by which AMP peptide enhances barrier function and structure were studied ex vivo using intestine and colon from mice given lipopolysaccharide (LPS), and in AMP-18 deficient mice given DSS. In interleukin-10 deficient mice given piroxicam, AMP peptide enhanced recovery after weight loss, protected against colon shortening and segmental dilation, and reduced the colitis activity score. In the T cell transfer model, treatment with the peptide protected against colon shortening. In mice given LPS in vivo to induce gut injury, AMP peptide prevented the onset of, and reversed established intestinal hyperpermeability by targeting TJ proteins and perijunctional actin. AMP-18-deficient mice challenged with DSS exhibited increased mortality, developed erosions in the colon, and had lower levels of ZO-1 in TJs than heterozygous littermates or wild-type mice. The results indicate that AMP-18/peptide may serve a protective role against injury along the GI mucosal barrier, and recommend further development of AMP peptide as a novel agent to treat patients with IBD.