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

Abstract

Background: MMPs have roles in inflammatory processes, extracellular matrix (ECM) remodelling, cellular proliferation and cancer invasion and metastasis. All these processes are relevant to the architectural disturbances seen in the gastric mucosa in response to H. pylori infection and it’s associated diseases. Whereas upregulation of a number of MMPs has been reported in H. pylori infection, there have been no detailed reports regarding altered production of their inhibitors, the Tissue Inhibitors of Metalloproteinases (TIMPs). The aim of this study was to investigate changes in the abundance of TIMPs in human gastric corpus and murine stomach in Helicobacter infection and to study cellular sources.

Methods: We obtained gastric corpus biopsies at endoscopy and assessed abundance of either mRNA or protein for TIMPs -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 TIMPs -1,-3 and -4 were examined by indirect immunohistochemistry. Circulating gastrin was measured by RIA. In addition, we compared abundance of TIMP-1, -3 and -4 mRNA in the stomach of H. felis-infected INS-GAS mice with that of uninfected control animals at three and six months post-infection.

Results: Compared to uninfected patients, mRNA and protein for TIMPs -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 MMP-8. Immunohistochemistry showed TIMP proteins localised to gastric epithelial cells (TIMP-1 and -3 confined to glandular cells, whereas TIMP-4 staining was also seen at the surface), 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 up-regulation of specific TIMPs, notably TIMPs -1 and -3 in glandular epithelium and stroma. We suggest that increased expression of specific protease inhibitors in the corpus mucosa may exert important effects on ECM remodelling and influence the outcome of H. pylori infection.