Helicobacter pylori causes chronic active gastritis and ulceration and has been associated with the development of gastric cancer and gastric MALT lymphoma in a subpopulation of humans. In many areas of the world, gastric cancer causes significant morbidity and mortality in humans. Gastric cancer development is a multistep process similar to that proposed for colorectal cancer, and an important aspect of gastric carcinogenesis is proliferation of gastric epithelial cells. Gastric epithelial proliferation in combination with DNA damage can result in development of neoplasia. The inflammatory milieu of Helicobacter pylori infection is complex with elevated levels of proinflammatory cytokines. The role of proinflammatory cytokines such as interferon-gamma, tumor necrosis factor-alpha, and interleukin-1 in the development of pathologic gastric epithelial hyperplasia was investigated. In mouse models of Helicobacter pylori gastritis, CD4+ T-cells are necessary for gastric epithelial proliferation, CD4+ T-cells are a major component of the inflammatory infiltrate, and gastric epithelial apoptosis and expansion of the gastric proliferation zone was associated with the CD4+ inflammatory infiltrate. Proinflammatory cytokines had no direct proliferative effect. Interferon-gamma, tumor necrosis factor-alpha, and interleukin-1 alpha elicited decreased proliferation of gastric epithelial cells in culture, while interferon-gamma apparently accomplished this by causing apoptosis. Transcript levels of interferon-gamma and its receptor, tumor necrosis factor-alpha, lymphotoxin, interleukin-10, interleukin-12, keratinocyte growth factor and its receptor, and transforming growth factor-alpha were all elevated in infected recipient severe combined immunodeficient (SCID) and wild-type C57BL/6 mice compared to uninfected and non-recipient mice. Transcript levels supported an association between interferon-gamma and keratinocyte growth factor. An indirect role of proinflammatory cytokines was investigated by developing a primary gastric lamina proprial fibroblast cell line. The fibroblasts expressed keratinocyte growth factor upon treatment with recombinant tumor necrosis factor-alpha, interleukin-1 alpha, and H. pylori lipopolysaccharide, but not with interferon-gamma, supporting an important role of stromal fibroblasts in development of gastric epithelial proliferation. An important role of interferon-gamma secreted from CD4+ T-cells is not ruled out, since this cytokine is important in activation of macrophages that are a source of tumor necrosis factor-alpha, and interleukin-1 alpha. The results indicated that CD4+ T-cells and attendant cytokines released in response to Helicobacter pylori likely play an important role, albeit indirect, in the development of pathologic gastric epithelial hyperplasia induced by Helicobacter pylori infection. Helicobacter pylori causes chronic active gastritis and ulceration and has been associated with the development of gastric cancer and gastric MALT lymphoma in a subpopulation of humans. In many areas of the world, gastric cancer causes significant morbidity and mortality in humans. Gastric cancer development is a multistep process similar to that proposed for colorectal cancer, and an important aspect of gastric carcinogenesis is proliferation of gastric epithelial cells. Gastric epithelial proliferation in combination with DNA damage can result in development of neoplasia. The inflammatory milieu of Helicobacter pylori infection is complex with elevated levels of proinflammatory cytokines. The role of proinflammatory cytokines such as interferon-gamma, tumor necrosis factor-alpha, and interleukin-1 in the development of pathologic gastric epithelial hyperplasia was investigated. In mouse models of Helicobacter pylori gastritis, CD4+ T-cells are necessary for gastric epithelial proliferation, CD4+ T-cells are a major component of the inflammatory infiltrate, and gastric epithelial apoptosis and expansion of the gastric proliferation zone was associated with the CD4+ inflammatory infiltrate. Proinflammatory cytokines had no direct proliferative effect. Interferon-gamma, tumor necrosis factor-alpha, and interleukin-1 alpha elicited decreased proliferation of gastric epithelial cells in culture, while interferon-gamma apparently accomplished this by causing apoptosis. Transcript levels of interferon-gamma and its receptor, tumor necrosis factor-alpha, lymphotoxin, interleukin-10, interleukin-12, keratinocyte growth factor and its receptor, and transforming growth factor-alpha were all elevated in infected recipient severe combined immunodeficient (SCID) and wild-type C57BL/6 mice compared to uninfected and non-recipient mice. Transcript levels supported an association between interferon-gamma and keratinocyte growth factor. An indirect role of proinflammatory cytokines was investigated by developing a primary gastric lamina proprial fibroblast cell line. The fibroblasts expressed keratinocyte growth factor upon treatment with recombinant tumor necrosis factor-alpha, interleukin-1 alpha, and H. pylori lipopolysaccharide, but not with interferon-gamma, supporting an important role of stromal fibroblasts in development of gastric epithelial proliferation. An important role of interferon-gamma secreted from CD4+ T-cells is not ruled out, since this cytokine is important in activation of macrophages that are a source of tumor necrosis factor-alpha, and interleukin-1 alpha. The results indicated that CD4+ T-cells and attendant cytokines released in response to Helicobacter pylori likely play an important role, albeit indirect, in the development of pathologic gastric epithelial hyperplasia induced by Helicobacter pylori infection.