Histidine decarboxylase (HDC), the unique enzyme responsible for histamine generation, is highly expressed in myeloid cells but its function is poorly understood. Here, we show that Hdc knockout mice exhibit a markedly increased rate of colon and skin carcinogenesis. Using Hdc-EGFP BAC transgenic mice, we demonstrate that Hdc is expressed primarily in CD11b+Ly6G+ immature myeloid cells (IMCs) that are recruited early on in chemical carcinogenesis. Transplant of Hdc-deficient bone marrow to wildtype recipients results in increased CD11b+Ly6G+ cell mobilization and reproduces the cancer susceptibility phenotype. In addition, IMCs from Hdc knockout mice promote the growth of cancer xenografts and colon cancer cells downregulate Hdc expression through promoter hypermethylation and inhibits myeloid cell maturation. Exogenous histamine induces the differentiation of IMCs and suppresses their ability to support the growth of xenografts. These data indicate key roles for Hdc and histamine in myeloid cell differentiation, and CD11b+Ly6G+ IMCs in early cancer development.

Interferon-gamma (IFN-γ) mediates responses to bacterial infection and autoimmune disease but it is also an important tumor suppressor. IFN-γ is upregulated in the gastric mucosa by chronic Helicobacter infection; however, whether it plays a positive or negative role in inflammation-associated gastric carcinogenesis is unexplored. To study this question we generated an H+/K+-ATPase-IFN-γ transgenic mouse that overexpresses murine IFN-γ in the stomach mucosa. In contrast to the expected pro-inflammatory role during infection, we found that IFN-γ overexpression failed to induce gastritis and instead inhibited gastric carcinogenesis induced by IL-1beta (IL-1β) and/or Helicobacter infection. Th1 and Th17 immune responses were inhibited by IFN-γ through Fas induction and apoptosis in CD4 T cells. IFN-γ also induced autophagy in gastric epithelial cells through increased expression of Beclin-1. Lastly, in the gastric epithelium, IFN-γ also inhibited IL-1β- and Helicobacter-induced epithelial apoptosis, proliferation, and Dckl1+ cell expansion. Taken together, our results suggest that IFN-γ coordinately inhibits bacterial infection and carcinogenesis in the gastric mucosa by suppressing putative gastric progenitor cell expansion and reducing epithelial cell apoptosis via induction of an autophagic program.