title: IL-10 deficiency leads to somatic mutations in a model of IBD.
abstract: Individuals with inflammatory bowel disease (IBD) are at increased risk of developing gastrointestinal cancer. Here, we have tested the possibility that chronic inflammation could trigger mutations. For this, we have used IL-10-deficient (IL-10-/-) mice, which spontaneously develop intestinal inflammation, in combination with a transgenic gpt gene and red/gam gene (gpt+IL-10-/-), which is a well-characterized mutation reporter locus. The total mutation frequency in the colon of gpt+IL-10-/- mice was about five times higher than that in normal gpt+IL-10+/+ mice. In the particular case of G:C to A:T transitions, the frequency of mutations in gpt+IL-10-/- mice was 4.1 times higher than that in control mice. Interestingly, the frequency of small deletions and insertions was also strikingly increased (approximately 10 times). The majority of the deletion or insertion mutations were observed in the monotonous base runs or adjacent repeats of short tandem sequences. In contrast, the frequency of large deletions, detected by loss of the Spi marker present in the red/gam transgene, was similar among the mouse strains. Finally, as a control, the mutation frequency in non-inflamed tissues, such as the liver, were similar between gpt+IL-10-/- mice and gpt+IL-10+/+ mice. Our data demonstrate that the chronic inflammatory environment in the colon promotes the generation of mutations.
authors.affiliation: Department of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan. ysatou@int3.med.tohoku.ac.jp
authors.forename: Yuichirou
authors.initials: Y
authors.lastname: Sato
authors.forename: Seiichi
authors.initials: S
authors.lastname: Takahashi
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Kinouchi
authors.forename: Manabu
authors.initials: M
authors.lastname: Shiraki
authors.forename: Katsuya
authors.initials: K
authors.lastname: Endo
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Matsumura
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Kakuta
authors.forename: Masaki
authors.initials: M
authors.lastname: Tosa
authors.forename: Atsuhiro
authors.initials: A
authors.lastname: Motida
authors.forename: Hiroko
authors.initials: H
authors.lastname: Abe
authors.forename: Go
authors.initials: G
authors.lastname: Imai
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yokoyama
authors.forename: Eiki
authors.initials: E
authors.lastname: Nomura
authors.forename: Kenichi
authors.initials: K
authors.lastname: Negoro
authors.forename: Sho
authors.initials: S
authors.lastname: Takagi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aihara
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Masumura
authors.forename: Takehiko
authors.initials: T
authors.lastname: Nohmi
authors.forename: Tooru
authors.initials: T
authors.lastname: Shimosegawa
mesh_terms: D000818:Animals; D003110:Colonic Neoplasms / Q000235:genetics; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D005260:Female; D017353:Gene Deletion; D005787:Gene Frequency; D017930:Genes, Reporter; D007249:Inflammation; D015212:Inflammatory Bowel Diseases / Q000235:genetics*; D016753:Interleukin-10 / Q000235:genetics* / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation
chemical_list: D016753:Interleukin-10