Yang Ying H, Wu William K K, Tai Emily K K, Wong Helen P S, Lam Emily K Y, So Wallace H L, Shin Vivian Y, Cho Chi H
Department of Pharmacology, Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Hong Kong, China.
J Pharmacol Exp Ther. 2006 Aug;318(2):547-54. doi: 10.1124/jpet.106.102467. Epub 2006 May 2.
Cathelicidin, a cationic host defense peptide, has been shown to promote cutaneous wound repair and reaches high levels in the gastric mucosa during infection and inflammation. Therefore, we investigated whether this peptide contributes to gastric ulcer healing in rats. Ulcer induction increased the expression of rat cathelicidin rCRAMP in the gastric mucosa. Further increase in expression of rCRAMP by local injection of rCRAMP-encoding plasmid promoted ulcer healing by enhancing cell proliferation and angiogenesis. rCRAMP directly stimulated proliferation of cultured rat gastric epithelial cells (RGM-1), which was abolished by inhibitors of matrix metalloproteinase (MMP), epidermal growth factor receptors (EGFR) tyrosine kinase, or mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase. rCRAMP also increased EGFR and ERK1/2 phosphorylation via an MMP-dependent mechanism. Knockdown of transforming growth factor alpha (TGFalpha), which is a ligand of EGFR, by small interfering RNA completely nullified the mitogenic signals evoked by rCRAMP in RGM-1 cells. These findings suggest that rCRAMP exhibits prohealing activity in stomachs through TGFalpha-dependent transactivation of EGFR and its related signaling pathway to induce proliferation of gastric epithelial cells.
杀菌肽是一种阳离子宿主防御肽，已被证明可促进皮肤伤口修复，且在感染和炎症期间胃黏膜中含量很高。因此，我们研究了这种肽是否有助于大鼠胃溃疡的愈合。诱导溃疡会增加大鼠胃黏膜中大鼠杀菌肽rCRAMP的表达。通过局部注射编码rCRAMP的质粒进一步增加rCRAMP的表达，可通过增强细胞增殖和血管生成来促进溃疡愈合。rCRAMP直接刺激培养的大鼠胃上皮细胞（RGM-1）的增殖，而基质金属蛋白酶（MMP）抑制剂、表皮生长因子受体（EGFR）酪氨酸激酶抑制剂或丝裂原活化蛋白激酶/细胞外信号调节激酶（ERK）激酶抑制剂可消除这种增殖。rCRAMP还通过MMP依赖的机制增加EGFR和ERK1/2的磷酸化。通过小干扰RNA敲低作为EGFR配体的转化生长因子α（TGFα），可完全消除rCRAMP在RGM-1细胞中引发的促有丝分裂信号。这些发现表明，rCRAMP通过EGFR的TGFα依赖性反式激活及其相关信号通路在胃中表现出促进愈合的活性，从而诱导胃上皮细胞增殖。
