TREFOIL PEPTIDES PROMOTE EPITHELIAL MIGRATION THROUGH A TRANSFORMING GROWTH-FACTOR BETA-INDEPENDENT PATHWAY
TREFOIL PEPTIDES PROMOTE EPITHELIAL MIGRATION THROUGH A TRANSFORMING GROWTH-FACTOR BETA-INDEPENDENT PATHWAY
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DOI：
10.1172/jci117332
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发表时间：
1994-07-01
影响因子：
15.9
通讯作者：
PODOLSKY, DK
中科院分区：
文献类型：
--
作者：
DIGNASS, A;LYNCHDEVANEY, K;PODOLSKY, DK
三叶肽是最近发现的一类抗蛋白酶多肽，在正常胃肠道中以区域特异性模式表达。虽然这些多肽被假设为生长因子，但它们的功能特性在很大程度上是未知的。在未转化的大鼠肠上皮细胞系(IEC-6和IEC-17)、人结肠癌来源的细胞系(HT-29和CaCO_2)或未转化的成纤维细胞(NRK和BHK)中加入重组三叶多肽-人痉挛多肽(HSP)、大鼠和人肠三叶因子(RITF和HITF)，对其增殖无明显影响。然而，在体外上皮修复模型中，将三叶肽添加到融合的IEC-6细胞损伤单层中，导致上皮迁移到伤口的速度增加了3-6倍。通过加入从大鼠或人的结肠或小肠中纯化的粘蛋白糖蛋白，三叶肽HSP以合作的方式增强了对修复的刺激，实现了高达15倍的修复。非粘蛋白糖蛋白的加入未见协同作用。与通过增强转化生长因子β生物活性介导的细胞因子刺激肠上皮细胞修复不同，三叶肽和三叶肽-粘蛋白糖蛋白促进肠上皮细胞修复与活性转化生长因子β浓度的改变无关，也不受免疫中和抗转化生长因子β抗血清的影响。总之，这些发现表明，分泌到胃肠道管腔表面的三叶肽可能与杯状细胞的粘蛋白糖蛋白产物共同作用，促进损伤后粘膜完整性的重建，其机制与作用于上皮基外侧极的机制不同。
The trefoil peptides, a recently recognized family of protease-resistant peptides, expressed in a regional specific pattern throughout the normal gastrointestinal tract. Although these peptides have been hypothesized to act as growth factors, their functional properties are largely unknown. Addition of recombinant trefoil peptides human spasmolytic polypeptide (HSP), rat and human intestinal trefoil factor (RITF and HITF) to subconfluent nontransformed rat intestinal epithelial cell Lines (IEC-6 and IEC-17), human colon cancer-derived cell lines (HT-29 and CaCO2) or nontransformed fibroblasts (NRK and BHK) had no significant effect on proliferation. However addition of the trefoil peptides to wounded monolayers of confluent IEC-6 cells in an in vitro model of epithelial restitution resulted in a 3-6-fold increase in the rate of epithelial migration into the wound. Stimulation of restitution by the trefoil peptide HSP was enhanced in a cooperative fashion by the addition of mucin glycoproteins purified from the colon or small intestine of either rat or man, achieving up to a 15-fold enhancement in restitution. No synergistic effect was observed by the addition of nonmucin glycoproteins. In contrast to cytokine stimulation of intestinal epithelial cell restitution which is mediated through enhanced TGF beta bioactivity, trefoil peptide, and trefoil peptide-mucin glycoprotein stimulation of restitution was not associated with alteration in concentrations of bioactive TGF-beta and was not affected by the presence of immunoneutralizing anti-TGF beta antiserum. Collectively, these findings suggest that the trefoil peptides which are secreted onto the lumenal surface of the gastrointestinal tract may act in conjunction with the mucin glycoprotein products of goblet cells to promote reestablishment of mucosal integrity after injury through mechanisms distinct from those which may act at the basolateral pole of the epithelium.