Varro, A.; Wroblewski, L.E.; Pagliocca, A.; Pritchard, D.M.; Noble, P.-J.M.; Hart, C.A.
April 2003
Gut;Apr2003 Supplement 1, Vol. 52, pA53
Academic Journal
Background and Aims: Epithelial cell responses to bacterial infection include induction of MMP-7. We have examined the cellular mechanisms of H pylori stimulation of MMP-7 in gastric cells, and the consequences for gastric epithelial cell migration. Methods: Gastric biopses of H pylori positive and negative subjects were probed for MMP-7 by Western blot. Biopsies were cull tured for up to 72hr and MMP-7 Iocalised by immunocytochemistry; cell migration in these cultures was examined by time lapse videomicroscopy. Cellular signalling mechanisms were examined using a MMP-7-promoter/luciferase (-luc) reporter vector transfected into AGS cells. Results: In H pylori positive patients there was increased MMP-7 in both corpus and antrum. MMP-7 was localised to mucus and chief (but not parietal or endocrine) cells in cultured gastric epithelial cells, and was identified in lamellipodia at the advancing edge of migrating ce s The spreading of gastric glands was significantly increased in H pylori positive cultures compared with control and migration was inhibited by MMP-7 antisense oligonucleotides. In addition, H pylori stimulated AGS cell migration and invasion and this was inhibited by an MMP-7 antibody. In AGS cells, H pylori induced expression of MMP-7-luc and this was significantly inhibited by co-transrection with dominant negative (DN-) forms of Rho and Rac, and by inhibitors of NFκ-B (BAY11-7082) and MEK (PD98059). A constitutively active (CA-) form of Rho also stimulated MMP-7-luc, and this was inhibited by BAY 11-7082, PD98059 and DN-Jun; in contrast, stimulation MMP-7-luc by CA-Rac was inhibited by BAY but not DN-Jun. Conclusions: 1. MMP-7 is increased in both corpus and antrum in response to H pylori. 2. MMP-7 plays a role in H pylori stimulated cell migration. 3. H pylori acts via RhoA, Rac, AP-1 and NFκB to stimulate MMP-7 expression.


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