Natural History of Gastric Mucosal Cytokine Expression inHelicobacter pyloriGastritis in Mongolian Gerbils

Abstract

Data regarding the chronological changes in gastric mucosal cytokines in the different phases of Helicobacter pylori infection are unavailable. We examined Mongolian gerbils for up to 52 weeks after H. pylori (ATCC 43504) inoculation. Levels of mRNAs of mucosal cytokines (interleukin-1␤ [IL-1␤], gamma interferon [IFN-␥], IL-4, IL-6, and IL-10) were assessed using real-time reverse transcription-PCR. Starting 26 weeks after H. pylori inoculation, two clinicohistologic patterns appeared: gastric ulcers in 32% and hyperplastic polyps in 68% of gerbils. High levels of mucosal IL-1␤ mRNA were observed early in the infection, reaching maximum at 4 weeks and then rapidly declining. Mucosal IFN-␥ mRNA also reached maximal levels at 4 weeks but remained high thereafter. Both IL-1␤ and IFN-␥ mRNA levels were consistently higher in the pyloric mucosa than in the fundic mucosa. In contrast, IL-4, IL-6, and IL-10 mRNA levels peaked at 8 to 26 weeks and levels were similar in the pyloric mucosa and the fundic mucosa. IFN-␥ mRNA levels were significantly higher in gerbils with ulcers than in those with hyperplastic polyps (median IFN-␥/glyceraldehyde-3-phosphate dehydrogenase ratio ؋ 100,000 ‫؍‬ 650 versus 338, respectively [antrum], and 172 versus 40, respectively [corpus]) (P < 0.05). We propose that the different outcomes (e.g., ulcers or hyperplastic polyps) might relate to imbalances among cytokines.Helicobacter pylori infection of the gastric mucosa is characterized by the infiltration of neutrophils, lymphocytes, monocytes, and plasma cells. The initial migration of inflammatory cells into the gastric mucosa and their activation are believed to depend on the production of proinflammatory cytokines (2,8,17,(30)(31)(32). The inflammatory products from the polymorphonuclear cells (PMNs) and mononuclear cells (MNCs) are also thought to damage the epithelial layer and play a role in disease pathogenesis. T-helper (Th) cells are also found in the gastric lamina propria in H. pylori infection. The cytokine response in the gastric mucosa of patients chronically infected with H. pylori is thought to be predominantly of the Th1 type (1,2,5,7,8,10,11,15,17,18,22,(24)(25)(26). This determination was based in part on the presence of increased numbers of gamma interferon (IFN-␥)-secreting T cells in H. pylori-infected gastric mucosa compared to normal mucosa (2,5,11,15,17,25). H. pylori-infected IFN-␥-knockout mice developed minimal pathological changes (1,22,24), consistent with the response to H. pylori infection being primarily a Th1-type response.However, the relative contribution of the different cytokines during the course of the infection is still unknown. It is generally impossible to characterize the natural history of the immune response to H. pylori in humans, but such studies are possible using animal models. Rodents are excellent model animals in that they can be infected with H. pylori strains that consistently produce severe gastritis. In particular, Mongolian gerbils (Meriones unguiculatus) infected with selected stra...

4‐Vinyl‐2,6‐dimethoxyphenol (canolol) suppresses oxidative stress and gastric carcinogenesis in Helicobacter pylori‐infected carcinogen‐treated Mongolian gerbils

“…However, gastric biopsies from persistently infected animals only showed weak gastritis. Yamaoka et al 25 have reported natural history of H. pylori (ATCC43504) induced gastritis and associated gastric mucosal cytokine expression in Mongolian gerbils. In their results, polymorphonuclear and mononuclear cell infiltration was apparent relatively early (8 and 4 weeks after inoculation, respectively) and declined thereafter.…”

“…It has been reported that a predominantly H. pylori-specific Th1 response, characterized by induction of high level of TNF-a, IL-1b, and IFN-g is associated with H. pylori-infected gastritis. 24,25 COX-2 and iNOS are well known to play important roles in gastric cancer growth and progression. These results indicate that canolol inhibits the mRNA expression of COX-2, upregulated by H. pylori-infection, and might reduce release of prostaglandin E2 from the gastric mucosa.…”

Pattern of Transcription Factor Activation in Helicobacter pylori–Infected Mongolian Gerbils

“…The culture of H pylori from the gastric mucosa of gerbils was performed as previously described. 9,11 The recovered strains were tested for chloramphenicol resistance to confirm the stability of the mutation for the cagE mutant-infected cases. Polymerase chain reaction (PCR) analysis was also performed for cagE mutants to confirm the preservation of chloramphenicol cassettes inside the target genes as previously described.…”

“…IFN-γ mRNA levels were decreased at 9 months, which differs from previous reports that IFN-γ mRNA levels remained high at 9 months. 9,28 The reason was unclear; however, the IFN-γ mRNA levels correlated well with cellular infiltration, ERK phosphorylation, and AP-1 binding activity. These results are consistent with the fact that the IFN-γ promoter is regulated primarily by AP-1.…”

“…The Mongolian gerbil (Meriones unguiculatus) has proven to be a convenient animal model for studies of H pylori infection because the gross and histologic findings mimic the lesions induced by H pylori infection in the human gastric mucosa. [5][6][7][8][9] In the present study, we investigated the roles of transcription factors in the gastric mucosa of H pylori-infected gerbils over the course of the infection in vivo.…”