Abstract
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 α (TGFα), 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 TGFα-dependent transactivation of EGFR and its related signaling pathway to induce proliferation of gastric epithelial cells.
Footnotes
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This work was supported by the Committee on Research and Conference Grants of the University of Hong Kong and The Hong Kong Research Grants Council (HKU 7397/03M).
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Y.H.Y. and W.K.K.W. contributed equally to this work.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.102467.
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ABBREVIATIONS: IL, interleukin; LPS, lipopolysaccharide; MMP, matrix metalloproteinase; GM6001, N-[(2R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl]-l-tryptophan methylamide; EGFR, epidermal growth factor receptor; AG1478, 4-(3-chloroanilino)-6,7-dimethoxyquinazoline; ERK, extracellular signal-regulated kinase; MEK, mitogen-activated protein kinase/extracellular signal-regulated kinase kinase; U0126, 1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene; PCNA, proliferating cell nuclear antigen; PAGE, polyacrylamide gel electrophoresis; EGF, epidermal growth factor; RT-PCR, reverse transcription-polymerase chain reaction; TGF, transforming growth factor; siRNA, small interfering RNA; HB-EGF, heparin-binding epidermal growth factor-like factor; ADAM, a disintegrin and metalloproteinase.
- Received February 6, 2006.
- Accepted April 28, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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