PROJECT SUMMARY Gastric atrophy and metaplasia are critical epithelial cell changes that promote gastric carcinogenesis. Gastric cancer is a major public health issue world-wide, being the third leading cause of cancer-related death in the world with nearly one million victims every year. Chronic inflammation is a major predisposing risk factor for the development of gastric cancer, demonstrated by the fact that patients with chronic atrophic gastritis have significantly higher risk of cancer than their healthy peers. While the association between chronic inflammation and cancer risk is clear, the exact mechanisms by which the inflammatory process in the stomach leads to carcinogenesis in some patients but not others are not understood. There is a complex cytokine milieu associated with any chronic inflammatory process, and polymorphisms in cytokine genes in human patients have been shown to have a significant effect on the risk of gastric cancer development. Due to the strong association between the prolonged cytokine production during inflammation and increased gastric cancer risk, we are interested in determining the mechanistic role that cytokines serve in regulating the development of gastric atrophy and metaplasia during chronic gastritis. Epstein-Barr Virus-Induced Gene 3 (Ebi3) encodes a protein subunit (EBI3) of the cytokine IL-27, which is well- characterized and has documented effects on CD4+ T cells during inflammation. EBI3 is also a component of the poorly understood immunosuppressive cytokine IL-35 thought to be made by regulatory T cells (Tregs). We use a novel murine model of inflammation-induced gastric atrophy and metaplasia, TxA23. In this model we have discovered that mice deficient in the production of Ebi3 have accelerated development of atrophy and spasmolytic polypeptide expressing metaplasia (SPEM), important preneoplastic epithelial cell lesions. We have also observed that Tregs, which are critical suppressors of gastritis and resulting lesions, exhibit a defective phenotype in Ebi3-/- mice. However, it is unclear whether this defect is due to the extrinsic lack of IL- 27 signaling or the intrinsic inability to express Ebi3, and thereby IL-35. Our hypothesis is that EBI3 expression is critical for suppressing the development of gastritis, gastric atrophy, and gastric metaplasia due in part to the effects of IL-27 acting on Tregs and increasing their suppressive functions. In Aim 1 we will determine whether IL-27 is the critical EBI3 containing cytokine responsible for suppressing disease progression. In Aim 2, we will determine the effect of IL-27 signaling into Tregs during the development of gastric atrophy and metaplasia.