Therapeutic potential of follistatin for colonic inflammation in mice
Therapeutic potential of follistatin for colonic inflammation in mice
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DOI：
10.1053/j.gastro.2004.11.063
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发表时间：
2005-02-01
期刊：
影响因子：
29.4
通讯作者：
Kojima, I
中科院分区：
文献类型：
--
作者：
Dohi, T;Ejima, C;Kojima, I
背景与目的：激活素属于转化生长因子-P超家族。最近的研究表明，激活素及其天然拮抗剂卵泡抑素参与组织修复和炎症过程。本研究的目的是确定用卵泡抑素中和激活素是否在几种结肠炎小鼠模型中具有体内抗炎作用。方法：我们评估了结肠内给予三硝基苯磺酸（TNBS）诱导的结肠炎中的激活素水平。我们随后测试了在TNBS结肠炎诱导之前或之后腹膜内注射卵泡抑素的效果。我们还检查了口服葡聚糖硫酸钠（DSS）诱导的结肠炎以及白细胞介素（IL）-10基因缺陷（IL-10（-/-））小鼠中发生的自发性结肠炎。结果：TNBS结肠炎急性期结肠中激活素转录物水平上调。上皮细胞、浸润性巨噬细胞（Mphi）和内皮细胞产生过量的激活素β A。用卵泡抑素预处理使TNBS结肠炎小鼠的存活率从33%增加到82%，并降低了IL-6和淀粉样蛋白A的血浆水平。给予卵泡抑素还降低了TNBS和DSS结肠炎的组织学评分和组织髓过氧化物酶活性，并降低了IL-10（-/-）小鼠结肠炎的严重程度。根据3种小鼠模型和体外实验的结果，卵泡抑素促进结肠上皮细胞的增殖。结论：卵泡抑素对激活素的中和作用促进上皮细胞分裂和组织修复，这清楚地表明了肠道炎症的治疗方式。
Background & Aims: Activins belong to the transforming growth factor-P superfamily. Recent studies have shown that activin and its natural antagonist, follistatin, are involved in tissue repair and inflammatory processes. The aim of this study was to determine whether neutralization of activins with follistatin would have an in vivo anti-inflammatory effect in several murine models of colitis. Methods: We assessed activin levels in the colitis induced by intracolonic administration of trinitrobenzene sulfonic acid (TNBS). We subsequently tested the effects of an intraperitoneal injection of follistatin before or after induction of TNBS colitis. We also examined the established colitis induced by oral dextran sulfate sodium (DSS) as well as the spontaneous colitis that develops in interleukin (IL)-10 gene-deficient (IL-10(-/-)) mice. Results: Levels of activin transcripts in the colon during the acute phase of TNBS colitis were up-regulated. Epithelial cells, infiltrating macrophages (Mphi), and endothelial cells produced excess activin betaA. Pretreatment with follistatin increased the survival rate of mice with TNBS colitis from 33% to 82% and decreased the plasma levels of IL-6 and amyloid A. Administration of follistatin also reduced the histologic score and tissue myeloperoxidase activity in established TNBS and DSS colitis and reduced the severity of the colitis in IL-10(-/-) mice. Based on results obtained from 3 mouse models and from in vitro experiments, follistatin promoted the proliferation of colonic epithelial cells. Conclusions: Neutralization of activins by follistatin promoted epithelial cell division and tissue repair, clearly suggesting a treatment modality for intestinal inflammation.