17 β-estradiol suppresses Helicobacter pylori-induced gastric pathology in male hypergastrinemic INS-GAS mice

• Published in: Carcinogenesis (New York) Vol. 32; no. 8; pp. 1244 - 1250
• Main Authors: Ohtani, Masahiro, Ge, Zhongming, García, Alexis, Rogers, Arlin B, Muthupalani, Sureshkumar, Taylor, Nancy S, Xu, Shilu, Watanabe, Koichiro, Feng, Yan, Marini, Robert P, Whary, Mark T, Wang, Timothy C, Fox, James G
• Format: Journal Article
• Language: English
• Published: England 01-08-2011
• Subjects: 17 beta -Estradiol; Age; Animals; Atrophy; Carcinogenesis; Castration; Dysplasia; Enzyme-Linked Immunosorbent Assay; Epithelium; Estradiol - therapeutic use; Estrogens; Estrogens - therapeutic use; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; Foxp3 protein; gamma -Interferon; Gastric cancer; Gastritis; Gastritis - etiology; Gastritis - pathology; Gastritis - prevention & control; Gene expression; Helicobacter; Helicobacter Infections - complications; Helicobacter Infections - immunology; Helicobacter Infections - pathology; Helicobacter pylori - pathogenicity; Hyperplasia; Immunoenzyme Techniques; Immunoglobulin G; Immunoregulation; Inflammation; Interferon-gamma - genetics; Interferon-gamma - metabolism; Interleukin 1; Interleukin 10; Interleukin-10 - genetics; Interleukin-10 - metabolism; Interleukin-1beta - genetics; Interleukin-1beta - metabolism; Intestinal Neoplasms - etiology; Intestinal Neoplasms - pathology; Intestinal Neoplasms - prevention & control; Intestine; Lymphocytes T; Male; Metaplasia; Metaplasia - etiology; Metaplasia - pathology; Metaplasia - prevention & control; Mice; Mice, Inbred C57BL; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Sex hormones; Stomach - immunology; Stomach - pathology; Stomach Neoplasms - etiology; Stomach Neoplasms - pathology; Stomach Neoplasms - prevention & control; Supplementation; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - microbiology; T-Lymphocytes, Regulatory - pathology; Testosterone - blood
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/bgr072

Helicobacter pylori-associated gastric cancer is male predominant and animal studies suggest that sex hormones influence gastric carcinogenesis. We investigated the effects of 17β-estradiol (E2) or castration on H.pylori-induced gastritis in male INS-GAS/FVB/N (Tg(Ins1-GAS)1Sbr) mice. Comparisons were made to previously evaluated sham (n = 8) and H.pylori-infected (n = 8), intact male INS-GAS mice which had developed severe corpus gastritis accompanied by atrophy, hyperplasia, intestinal metaplasia and dysplasia of the epithelium within 16 weeks postinfection (all P < 0.01). Castration at 8 weeks of age had no sparing effect on lesions in uninfected (n = 5) or H.pylori-infected mice (n = 7) but all lesion subfeatures were attenuated by E2 in H.pylori-infected mice (n = 7) (P < 0.001). Notably, inflammation was not reduced but glandular atrophy, hyperplasia, intestinal metaplasia and dysplasia were also less severe in uninfected, E2-treated mice (n = 7) (P < 0.01). Attenuation of gastric lesions by E2 was associated with lower messenger RNA (mRNA) expression of interferon (IFN)-γ (P < 0.05) and interleukin (IL)-1β (P < 0.004), and higher IL-10 (P < 0.02) as well as decreased numbers of Foxp3(+) regulatory T cells when compared with infected intact males. Infected E2-treated mice also developed higher Th2-associated anti-H.pylori IgG1 responses (P < 0.05) and significantly lower Ki-67 indices of epithelial proliferation (P < 0.05). E2 elevated expression of mRNA for Foxp3 (P < 0.0001) and IL-10 (P < 0.01), and decreased IL-1β (P < 0.01) in uninfected, intact male mice compared with controls. Therefore, estrogen supplementation, but not castration, attenuated gastric lesions in H.pylori-infected male INS-GAS mice and to a lesser extent in uninfected mice, potentially by enhancing IL-10 function, which in turn decreased IFN-γ and IL-1β responses induced by H.pylori.