title: 17 β-estradiol suppresses Helicobacter pylori-induced gastric pathology in male hypergastrinemic INS-GAS mice.
abstract: 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.
authors.affiliation: Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ohtani
authors.forename: Zhongming
authors.initials: Z
authors.lastname: Ge
authors.forename: Alexis
authors.initials: A
authors.lastname: García
authors.forename: Arlin B
authors.initials: AB
authors.lastname: Rogers
authors.forename: Sureshkumar
authors.initials: S
authors.lastname: Muthupalani
authors.forename: Nancy S
authors.initials: NS
authors.lastname: Taylor
authors.forename: Shilu
authors.initials: S
authors.lastname: Xu
authors.forename: Koichiro
authors.initials: K
authors.lastname: Watanabe
authors.forename: Yan
authors.initials: Y
authors.lastname: Feng
authors.forename: Robert P
authors.initials: RP
authors.lastname: Marini
authors.forename: Mark T
authors.initials: MT
authors.lastname: Whary
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Wang
authors.forename: James G
authors.initials: JG
authors.lastname: Fox
mesh_terms: D000818:Animals; D002369:Castration; D004797:Enzyme-Linked Immunosorbent Assay; D004958:Estradiol / Q000627:therapeutic use*; D004967:Estrogens / Q000627:therapeutic use; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D005756:Gastritis / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D016481:Helicobacter Infections / Q000150:complications* / Q000276:immunology / Q000473:pathology; D016480:Helicobacter pylori / Q000472:pathogenicity*; D007124:Immunoenzyme Techniques; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D007414:Intestinal Neoplasms / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D008297:Male; D008679:Metaplasia / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013270:Stomach / Q000276:immunology / Q000473:pathology; D013274:Stomach Neoplasms / Q000209:etiology / Q000473:pathology* / Q000517:prevention & control*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D013739:Testosterone / Q000097:blood
chemical_list: D004967:Estrogens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053583:Interleukin-1beta; D012333:RNA, Messenger; D016753:Interleukin-10; D013739:Testosterone; D004958:Estradiol; D007371:Interferon-gamma