Abstract
Helicobacter pylori are responsible for the induction of chronic gastric inflammation progressing to atrophy, metaplasia, and gastric cancer. The overexpression of Cathepsin X/Z (Ctsz) in H. pylori-infected mucosa and gastric cancer is mediated predominantly by an augmented migration of ctsz−/−positive macrophages and the up-regulation of Ctsz in tumor epithelium. To explore the Ctsz-function in the context of chronic inflammation and the development of preneoplastic lesions, we used Ctsz-deficient mice in a H. pylori gastritis model. Ctsz −/− and wild-type (wt) mice were infected with H. pylori strain SS1. The mice were sacrificed at 24, 36, and 50 weeks post infection (wpi). The stomach was removed, and gastric strips were snap-frozen or embedded and stained with H&E. Tissue sections were scored for epithelial lesions and inflammation. Ki-67 and F4/80 immunostaining were used to measure epithelial cell proliferation and macrophage infiltration, respectively. The upregulation of compensating cathepsins and cytokines were confirmed by Western blotting and quantitative RT-PCR. SS1-infected wt and ctsz −/− mice showed strong inflammation, foveolar hyperplasia, atrophy, and cystically-dilated glands. However, at 50 wpi, ctsz −/− mice developed significantly more severe spasmolytic polypeptide-expressing metaplasia (SPEM), showed enhanced epithelial proliferation, and higher levels of infiltrating macrophages. Induction of cytokines was higher and significantly prolonged in ctsz −/− mice compared to wt. Ctsz deficiency supports H. pylori-dependent development of chronic gastritis up to metaplasia, indicating a protective, but not proteolytic, function of Ctsz in inflammatory gastric disease.
Highlights
IntroductionThe H. pylori-dependent activation of diverse signaling cascades induces the upregulation of proinflammatory chemokines and induces morphological rearrangements of epithelial cells, resulting in chronic gastritis, which progresses from atrophy, to intestinal and spasmolytic metaplasia, dysplasia, and to cancer
Persistent H. pylori infection is one major cause of gastric cancer
Wt and ctsz2/2 mice were inoculated with either H. pylori Sydney strain-1 (SS1) or B128 strain (n = 49)
Summary
The H. pylori-dependent activation of diverse signaling cascades induces the upregulation of proinflammatory chemokines and induces morphological rearrangements of epithelial cells, resulting in chronic gastritis, which progresses from atrophy, to intestinal and spasmolytic metaplasia, dysplasia, and to cancer. This diverse clinical outcome may be associated with the expression of bacterial virulence factors. Proteolysis is instrumental for extracellular matrix (ECM) degradation during tumor invasion and metastasis. Due to its unique carboxypeptidase specificity, Ctsz is unable to participate in bulk ECM degradation, questioning its direct contribution to the invasive processes of tumor cells [13]. Recent findings indicate carboxyterminal processing of LFA-1 (integrin aL/b2) and bradikinin/kallidin, such that multifactorial interactions for Ctsz in immune response are proposed [18,19]
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