Abstract:Gastric adenocarcinoma is one of the leading causes of cancer mortality worldwide. It arises through a stepwise process that includes prominent inflammation with expression of interferon-γ (IFN-γ) and multiple other pro-inflammatory cytokines. We engineered mice expressing IFN-γ under the control of the stomach-specific H(+)/K(+) ATPase β promoter to test the potential role of this cytokine in gastric tumorigenesis. Stomachs of H/K-IFN-γ transgenic mice exhibited inflammation, expansion of myofibroblasts, loss… Show more
“…In the gastric mucosa after 3 weeks of infection, areas of inflammation and SPEM were visible and in some cases extensive (Figure 3) but were interspersed with patches of normal-appearing mucosa. Consistent with previous reports [36], SPEM in infected mice was characterized by the loss of specialized gland cells and expansion of metaplastic cells with abundant, “foamy” mucin-filled cytoplasm that stained purple/blue with periodic acid–Schiff/Alcian blue (Figure 3). Figure 3.Infection with SS1 s1i1 induces spasmolytic polypeptide-expressing metaplasia (SPEM) and inflammation in mouse gastric mucosa.…”
Carriage of Helicobacter pylori strains producing more active (s1/i1) forms of VacA is strongly associated with gastric adenocarcinoma. To our knowledge, we are the first to determine effects of different polymorphic forms of VacA on inflammation and metaplasia in the mouse stomach. Bacteria producing the less active s2/i2 form of VacA colonized mice more efficiently than mutants null for VacA or producing more active forms of it, providing the first evidence of a positive role for the minimally active s2/i2 toxin. Strains producing more active toxin forms induced more severe and extensive metaplasia and inflammation in the mouse stomach than strains producing weakly active (s2/i2) toxin. We also examined the association in humans, controlling for cagPAI status. In human gastric biopsy specimens, the vacA i1 allele was strongly associated with precancerous intestinal metaplasia, with almost complete absence of intestinal metaplasia in subjects infected with i2-type strains, even in a vacA s1, cagA+ background.
“…In the gastric mucosa after 3 weeks of infection, areas of inflammation and SPEM were visible and in some cases extensive (Figure 3) but were interspersed with patches of normal-appearing mucosa. Consistent with previous reports [36], SPEM in infected mice was characterized by the loss of specialized gland cells and expansion of metaplastic cells with abundant, “foamy” mucin-filled cytoplasm that stained purple/blue with periodic acid–Schiff/Alcian blue (Figure 3). Figure 3.Infection with SS1 s1i1 induces spasmolytic polypeptide-expressing metaplasia (SPEM) and inflammation in mouse gastric mucosa.…”
Carriage of Helicobacter pylori strains producing more active (s1/i1) forms of VacA is strongly associated with gastric adenocarcinoma. To our knowledge, we are the first to determine effects of different polymorphic forms of VacA on inflammation and metaplasia in the mouse stomach. Bacteria producing the less active s2/i2 form of VacA colonized mice more efficiently than mutants null for VacA or producing more active forms of it, providing the first evidence of a positive role for the minimally active s2/i2 toxin. Strains producing more active toxin forms induced more severe and extensive metaplasia and inflammation in the mouse stomach than strains producing weakly active (s2/i2) toxin. We also examined the association in humans, controlling for cagPAI status. In human gastric biopsy specimens, the vacA i1 allele was strongly associated with precancerous intestinal metaplasia, with almost complete absence of intestinal metaplasia in subjects infected with i2-type strains, even in a vacA s1, cagA+ background.
“…35 Using a similar model to overexpress IFNγ, Syu et al reported IFNγ induced metaplasia. 38 In the present study, L635-treated IFNγKO mice developed SPEM similar to wild type mice. The difference in our findings may depend on experimental conditions used to induce parietal cell loss.…”
Background & Aims
Loss of parietal cells causes the development of spasmolytic polypeptide-expressing metaplasia (SPEM), through transdifferentiation of chief cells. In the presence of inflammation, SPEM can advance into a more proliferative metaplasia with increased expression of intestine-specific transcripts. We used L635 to induce acute SPEM with inflammation in mice and investigated the roles of inflammatory cells in the development of SPEM.
Methods
To study the adaptive immune system, Rag1 knockout (Rag1KO), interferon g-deficient (IFNgKO), and wild type (control) mice received L635 for 3 days. To study the innate immune system, macrophages were depleted by intraperitoneal injection of clodronate liposomes 2 days before and throughout L635 administration. Neutrophils were depleted by intraperitoneal injection of an antibody against Ly6G 2 days before and throughout L635 administration. Pathology and immunohistochemical analyses were used to determine depletion efficiency, metaplasia, and proliferation. To characterize SPEM in each model, gastric tissues were collected and levels of Cftr, Dmbt1, and Gpx2 mRNAs were measured. Markers of macrophage polarization were used to identify subpopulations of macrophages recruited to the gastric mucosa.
Results
Administration of L635 to Rag1KO, IFNgKO, and neutrophil-depleted mice led to development of proliferative SPEM and upregulation of intestine-specific transcripts in SPEM cells, similar to controls. However, macrophage-depleted mice given L635 showed significant reductions in numbers of SPEM cells, SPEM cell proliferation, and expression of intestine-specific transcripts, compared with control mice given L635. In mice given L635, as well as patients with intestinal metaplasia, M2 macrophages were the primary inflammatory component.
Conclusion
Results from studies of mouse models and human metaplastic tissues indicate that M2 macrophages promote the advancement of SPEM in the presence of inflammation.
“…25,26 Notably, there is considerable evidence that elevated expression of IL-1β, IFN-γ, and TNF-α are associated with chronic gastritis and gastric cancer development following HP infection. 7,11,25,27,28 Our study revealed that OPN expression was elevated in response to HP infection, and OPN depletion decreased production of these cytokines in both gastric epithelial cells and macrophages during HP infection. These results suggest that OPN is an important mediator of proinflammatory cytokine production during HP infection.…”
Osteopontin (OPN) is a multifunctional protein that plays a role in many physiological and pathological processes, including inflammation and tumorigenesis. Here, we investigated the involvement of OPN in Helicobacter pylori (HP)-induced gastritis using OPN knockout (KO) mice and OPN knockdown (KD) cell lines. HP-infected OPN KO mice showed significantly reduced gastritis compared with wild-type (WT) mice with decreased infiltration of macrophages and a reduction in HP-induced upregulation of IL-1β, TNF-α, and IFN-γ. HP-exposed OPN KD gastric cancer cells and macrophage-like cells showed an attenuated induction of these cytokines. We also demonstrated a reduction in the migration of monocytic and macrophage-like cells toward conditioned media harvested from HP-exposed OPN KD gastric cancer cells as well as reduced migration ability of OPN KD cells itself. In addition, HP-infected OPN KO mice showed decreased epithelial cell proliferation compared with HP-infected WT mice, in association with a reduction in MAPK pathway activation. OPN KD gastric cancer cell lines also showed lower proliferative activity and reduced MAPK activation than shRNA control cells after HP co-culture or after IL-1β and TNF-α treatment. Taken together, these results indicate that OPN exerts a considerable influence on HP-induced gastritis by modulating the production of cytokines and contributing to macrophage infiltration. Moreover, OPN-mediated activation of the MAPK pathway in gastric epithelial cells might contribute to epithelial changes following HP infection. Helicobacter pylori (HP) is a Gram-negative bacterial pathogen that selectively colonizes the human stomach. 1,2 Approximately half of the world's population is infected with HP, and its infection is strongly associated with chronic gastritis, peptic ulcers, and gastric cancer. 1,2 HP-infected gastric mucosa progresses through stages of chronic gastritis, glandular atrophy, intestinal metaplasia, dysplasia, and gastric cancer. 3 HP produce a variety of virulence factors such as CagA and VacA that can affect host intracellular signaling pathways and play an important role in determining the outcome of HP infection. 3 However, they are not absolute determinants of clinical outcomes because most individuals remain asymptomatic after HP infection. 4 The variable outcomes of HP infection can be attributed to inflammatory responses governed by host factors as well as HP virulence factors. 5 Indeed, polymorphisms of host interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) are reported to be associated with the risk of HP-associated gastric cancer development. 4 HP-induced chronic inflammation induces DNA alterations and imbalanced epithelial cell turnover, providing opportunities for mitotic error that could ultimately contribute to the development of gastric cancer. 3,[6][7][8] Infiltrating macrophages, in particular, produce various cytokines and growth factors such as IL-1β that could attract more inflammatory cells and induces the proliferation of gastric epithelial cells....
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