title: Helicobacter pylori stimulates gastric epithelial cell MMP-1 secretion via CagA-dependent and -independent ERK activation.
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.
authors.affiliation: Department of Medicine, New York University School of Medicine, New York, New York 10016, USA. michael.pillinger@med.nyu.edu
authors.forename: Michael H
authors.initials: MH
authors.lastname: Pillinger
authors.forename: Nada
authors.initials: N
authors.lastname: Marjanovic
authors.forename: Seok-Yong
authors.initials: SY
authors.lastname: Kim
authors.forename: Yong-Chan
authors.initials: YC
authors.lastname: Lee
authors.forename: Jose U
authors.initials: JU
authors.lastname: Scher
authors.forename: Jatin
authors.initials: J
authors.lastname: Roper
authors.forename: Aryeh M
authors.initials: AM
authors.lastname: Abeles
authors.forename: Peter I
authors.initials: PI
authors.lastname: Izmirly
authors.forename: Matthew
authors.initials: M
authors.lastname: Axelrod
authors.forename: Mara Y
authors.initials: MY
authors.lastname: Pillinger
authors.forename: Sonia
authors.initials: S
authors.lastname: Tolani
authors.forename: Victoria
authors.initials: V
authors.lastname: Dinsell
authors.forename: Steven B
authors.initials: SB
authors.lastname: Abramson
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Blaser
mesh_terms: D000942:Antigens, Bacterial / Q000235:genetics / Q000378:metabolism*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000201:enzymology / Q000382:microbiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005838:Genotype; D016481:Helicobacter Infections / Q000378:metabolism / Q000382:microbiology*; D016480:Helicobacter pylori / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D009375:Neoplasms, Glandular and Epithelial; D013274:Stomach Neoplasms; D014162:Transfection; D014774:Virulence
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; C080866:cagA protein, Helicobacter pylori; D048049:Extracellular Signal-Regulated MAP Kinases; D020781:Matrix Metalloproteinase 1