Helicobacter pylori stimulates gastric epithelial cell MMP-1 secretion via CagA-dependent and -independent ERK activation

Michael H. Pillinger, Nada Marjanovic, Seok Yong Kim, Yong Chan Lee, Jose U. Scher, Jatin Roper, Aryeh M. Abeles, Peter I. Izmirly, Matthew Axelrod, Mara Y. Pillinger, Sonia Tolani, Victoria Dinsell, Steven B. Abramson, Martin J. Blaser

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Abstract

Because the mechanisms of Helicobacter pylori-induced gastric injury are incompletely understood, we examined the hypothesis that H. pylori induces matrix metalloproteinase-1 (MMP-1) secretion, with potential to disrupt gastric stroma. We further tested the role of CagA, an H. pylori virulence factor, in MMP-1 secretion. Co-incubation of AGS cells with Tx30a, an H. pylori strain lacking the cagA virulence gene, stimulated MMP-1 secretion, confirming cagA-independent secretion. Co-incubation with strain 147C (cagA+) resulted in CagA translocation into AGS cells and increased MMP-1 secretion relative to Tx30a. Transfection of cells with the recombinant 147C cagA gene also induced MMP-1 secretion, indicating that CagA can independently stimulate MMP-1 secretion. Co-incubation with strain 147A, containing a cagA gene that lacks an EPIYA tyrosine phosphorylation motif, as well as transfection with 147A cagA, yielded an MMP-1 secretion intermediate between no treatment and 147C, indicating that CagA tyrosine phosphorylation regulates cellular signaling in this model system. H. pylori induced activation of the MAP kinase ERK, with CagA-independent (early) and dependent (later) components. MEK inhibitors UO126 and PD98059 inhibited both CagA-independent and -dependent MMP-1 secretion, whereas p38 inhibition enhanced MMP-1 secretion and ERK activation, suggesting p38 negative regulation of MMP-1 and ERK. These data indicate H. pylori effects on host epithelial MMP-1 expression via ERK, with p38 playing a potential regulatory role.

Original languageEnglish
Pages (from-to)18722-18731
Number of pages10
JournalJournal of Biological Chemistry
Volume282
Issue number26
DOIs
Publication statusPublished - 2007 Jun 29

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Pillinger, M. H., Marjanovic, N., Kim, S. Y., Lee, Y. C., Scher, J. U., Roper, J., Abeles, A. M., Izmirly, P. I., Axelrod, M., Pillinger, M. Y., Tolani, S., Dinsell, V., Abramson, S. B., & Blaser, M. J. (2007). Helicobacter pylori stimulates gastric epithelial cell MMP-1 secretion via CagA-dependent and -independent ERK activation. Journal of Biological Chemistry, 282(26), 18722-18731. https://doi.org/10.1074/jbc.M703022200