Helicobacter pylori-Induced Mucosal Inflammation Is Th1 Mediated and Exacerbated in IL-4, But Not IFN-γ, Gene-Deficient Mice

Abstract

To elucidate the pathogenesis of Helicobacter pylori-associated gastritis, we studied immune responses of C57BL/6J wild-type (WT), SCID, and gene deficient (IFN-γ−/− and IL-4−/−) mice following infection with a pathogenic isolate of H. pylori (SPM326). During early infection in WT mice, mononuclear and polymorphonuclear cells accumulated in the gastric lamina propria, and the numbers of cells in the inflamed mucosa expressing IFN-γ, but not IL-4, mRNA rose significantly (p < 0.005), consistent with a local Th1 response. Splenic T cells from the same infected WT mice produced high levels of IFN-γ, no detectable IL-4, and low amounts of IL-10 following in vitro H. pylori urease stimulation, reflecting a systemic Th1 response. Infected C57BL/6J SCID mice did not develop gastric inflammation despite colonization by many bacteria. Infected C57BL/10J and BALB/c mice also did not develop gastric inflammation and displayed a mixed Th1/Th2 splenic cytokine profile. These data imply a major role for the Th1 cytokine IFN-γ in H. pylori-associated gastric inflammation in C57BL/6J mice. Compared with WT animals, infected IL-4−/− animals had more severe gastritis and higher levels of IFN-γ production by urease-stimulated splenocytes (p < 0.01), whereas IFN-γ−/− mice exhibited no gastric inflammation and higher levels of IL-4 production by stimulated splenocytes. These findings establish C57BL/6J mice as an important model for H. pylori infection and demonstrate that up-regulated production of IFN-γ, in the absence of the opposing effects of IL-4 (and possibly IL-10), plays a pivotal role in promoting H. pylori-induced mucosal inflammation.

Gene expression profiling in human gastric mucosa infected with Helicobacter pylori

“…First, infection was associated with an upregulation of genes encoding complement proteins, namely C2, C3, C4a, and factor B, suggesting that H. pylori engages both the 37 In fact, close analysis of the CD4 T-cell response revealed that the specific Th2-polarized response mediates protective immunity, in contrast to the Th1 response induced by H. pylori, which is ineffective in combating infection. 28,38 In addition, it has been suggested that the Th1 response may also mediate gastritis and gastric cancer. 39 Several studies have shown that T lymphocytes of Stat6-deficient mice fail to differentiate into Th2 cells in response to IL-4 or IL-13.…”

Role of Tumor Necrosis Factor‐Alpha and Interferon‐Gamma in Helicobacter pylori Infection

“…On the other hand, IL-4 does not seem to be critical in H. pylori infection (1,5,20), whereas it plays an important role in H. felis infection of mice (22), and Smythies et al (29) found stronger gastric inflammation in IL-4-deficient mice. Chen et al reported significantly reduced colonization of the gastric mucosa in IL-10-deficient mice so that IL-10 seemed to be an inhibitor of the protective immune response to H. pylori infection (6).…”

Inflammation, atrophy, and gastric cancer

“…(74), whereas mouse strains resistant to gastric atrophy, such as BALB/c mice, mount Th2 cell responses. Third, deletion of the gene encoding the Th1 cytokine IFN-γ protects mice from gastric atrophy induced by infection with Helicobacter spp., whereas deletion of the gene encoding the Th2 cytokine IL-4 leads to more severe atrophic gastritis (75). Finally, infusion of IFN-γ into C57BL/6 mice can induce metaplasia and SPEM (76), whereas pretreatment of mice with IL-4 prevents the development of atrophic gastritis after infection with Helicobacter spp.…”