Altered gastric corpus expression of tissue inhibitors of metalloproteinases in human and murine Helicobacter infection

Background: Matrix metalloproteinases (MMPs) have roles in inflammation and other processes relevant to the architectural disturbances seen in the gastric mucosa in response to Helicobacter pylori infection. Upregulation of MMPs has been reported in H pylori infection, but there are no detailed reports regarding altered production of their inhibitors, the tissue inhibitors of metalloproteinases (TIMPs). Aims: To investigate changes in the abundance of TIMPs in human gastric corpus mucosa and murine stomach in Helicobacter infection, and to study cellular sources in man. Methods: Gastric corpus biopsy samples were assessed for abundance of mRNA or protein for TIMP-1 to -4 by real-time quantitative PCR or western blotting, respectively. Antral and corpus biopsies were processed for histology, H pylori status and inflammatory scoring. Cellular sources of TIMP-1, -3 and -4 were examined by indirect immunohistochemistry. Circulating gastrin was measured by radioimmunoassay. Also, abundance of TIMP-1, -3 and -4 mRNA in the stomach of Helicobacter felis infected mice post-infection was compared with that of uninfected control animals. Results: Compared with uninfected patients, mRNA and protein for TIMP-1, -3 and -4 were significantly more abundant in the gastric corpus of H pylori infected subjects. Gastric TIMP expression did not differ significantly between hyper-and normogastrinaemic subjects within the H pylori negative and positive groups. There was no difference in mRNA abundance for MMP-3 or-8. Immunohistochemistry showed TIMP proteins localised to gastric epithelial, stromal cells and inflammatory cells. Murine H felis infection was associated with upregulation of TIMP-1 and-3 mRNA. Conclusions: Helicobacter infection is associated with upregulation of specific TIMPs (TIMP-1 and-3) in glandular epithelium and stroma. It is suggested that increased expression of specific protease inhibitors in the corpus mucosa may exert important effects on extracellular matrix remodelling and influence the outcome of H pylori infection.