IL-10 deficiency leads to somatic mutations in a model of IBD.
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.
Sato
Yuichirou
Y
Department of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan. ysatou@int3.med.tohoku.ac.jp
Takahashi
Seiichi
S
Kinouchi
Yoshitaka
Y
Shiraki
Manabu
M
Endo
Katsuya
K
Matsumura
Yoshifumi
Y
Kakuta
Yoichi
Y
Tosa
Masaki
M
Motida
Atsuhiro
A
Abe
Hiroko
H
Imai
Go
G
Yokoyama
Hiroshi
H
Nomura
Eiki
E
Negoro
Kenichi
K
Takagi
Sho
S
Aihara
Hiroyuki
H
Masumura
Ken-ichi
K
Nohmi
Takehiko
T
Shimosegawa
Tooru
T
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
D016753:Interleukin-10