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Tamoxifen (TAM) has recently been shown to cause acute gastric atrophy and metaplasia in mice. We have previously demonstrated that the outcome of  Helicobacter felis  infection, which induces similar gastric lesions in mice, is altered by deletion of specific NF- κ B subunits.  Nfkb1   −/−   mice developed more severe gastric atrophy than wild-type (WT) mice 6 weeks after  H. felis  infection. In contrast,  Nfkb2   −/−   mice were protected from this pathology. We therefore hypothesized that gastric lesions induced by TAM may be similarly regulated by signaling via NF- κ B subunits. Groups of five female C57BL/6 (WT),  Nfkb1   −/−  ,  Nfkb2   −/−   and  c-Rel   −/−   mice were administered 150 mg/kg TAM by IP injection. Seventy-two hours later, gastric corpus tissues were taken for quantitative histological assessment. In addition, groups of six female WT and  Nfkb1   −/−   mice were exposed to 12 Gy  γ -irradiation. Gastric epithelial apoptosis was quantified 6 and 48 h after irradiation. TAM induced gastric epithelial lesions in all strains of mice, but this was more severe in  Nfkb1   −/−   mice than in WT mice.  Nfkb1   −/−   mice exhibited more severe parietal cell loss than WT mice, had increased gastric epithelial expression of Ki67 and had an exaggerated gastric epithelial DNA damage response as quantified by  γ H2AX. To investigate whether the difference in gastric epithelial DNA damage response of  Nfkb1   −/−   mice was unique to TAM-induced DNA damage or a generic consequence of DNA damage, we also assessed gastric epithelial apoptosis following  γ -irradiation. Six hours after  γ -irradiation, gastric epithelial apoptosis was increased in the gastric corpus and antrum of  Nfkb1   −/−   mice. NF- κ B1-mediated signaling regulates the development of gastric mucosal pathology following TAM administration. This is associated with an exaggerated gastric epithelial DNA damage response. This aberrant response appears to reflect a more generic sensitization of the gastric mucosa of  Nfkb1   −/−   mice to DNA damage.

Mice lacking NF-κB1 exhibit marked DNA damage responses and more severe gastric pathology in response to intraperitoneal tamoxifen administration