title: Interleukin-22 drives nitric oxide-dependent DNA damage and dysplasia in a murine model of colitis-associated cancer.
abstract: The risk of colon cancer is increased in patients with Crohn's disease and ulcerative colitis. Inflammation-induced DNA damage could be an important link between inflammation and cancer, although the pathways that link inflammation and DNA damage are incompletely defined. RAG2-deficient mice infected with Helicobacter hepaticus (Hh) develop colitis that progresses to lower bowel cancer. This process depends on nitric oxide (NO), a molecule with known mutagenic potential. We have previously hypothesized that production of NO by macrophages could be essential for Hh-driven carcinogenesis, however, whether Hh infection induces DNA damage in this model and whether this depends on NO has not been determined. Here we demonstrate that Hh infection of RAG2-deficient mice rapidly induces expression of iNOS and the development of DNA double-stranded breaks (DSBs) specifically in proliferating crypt epithelial cells. Generation of DSBs depended on iNOS activity, and further, induction of iNOS, the generation of DSBs, and the subsequent development of dysplasia were inhibited by depletion of the Hh-induced cytokine IL-22. These results demonstrate a strong association between Hh-induced DNA damage and the development of dysplasia, and further suggest that IL-22-dependent induction of iNOS within crypt epithelial cells rather than macrophages is a driving force in this process.
authors.affiliation: Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: C
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: G
authors.initials: G
authors.lastname: Gong
authors.affiliation: Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: A
authors.initials: A
authors.lastname: Sheh
authors.affiliation: Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: S
authors.initials: S
authors.lastname: Muthupalani
authors.affiliation: Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: E M
authors.initials: EM
authors.lastname: Bryant
authors.affiliation: Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Puglisi
authors.affiliation: Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: H
authors.initials: H
authors.lastname: Holcombe
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: E A
authors.initials: EA
authors.lastname: Conaway
authors.affiliation: Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: N A P
authors.initials: NAP
authors.lastname: Parry
authors.affiliation: Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: V
authors.initials: V
authors.lastname: Bakthavatchalu
authors.affiliation: Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, and Department of Cancer Biology, Vanderbilt University Medical School, Nashville, Tennessee, USA.
authors.forename: S P
authors.initials: SP
authors.lastname: Short
authors.affiliation: Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, and Department of Cancer Biology, Vanderbilt University Medical School, Nashville, Tennessee, USA.
authors.forename: C S
authors.initials: CS
authors.lastname: Williams
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: G N
authors.initials: GN
authors.lastname: Wogan
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: S R
authors.initials: SR
authors.lastname: Tannenbaum
authors.affiliation: Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: J G
authors.initials: JG
authors.lastname: Fox
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: B H
authors.initials: BH
authors.lastname: Horwitz
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage; D003093:Colitis, Ulcerative / Q000150:complications / Q000276:immunology*; D003106:Colon / Q000473:pathology* / Q000503:physiopathology; D003110:Colonic Neoplasms / Q000150:complications / Q000276:immunology*; D053903:DNA Breaks, Double-Stranded; D004268:DNA-Binding Proteins / Q000235:genetics; D004195:Disease Models, Animal; D016481:Helicobacter Infections / Q000150:complications / Q000276:immunology*; D044923:Helicobacter hepaticus / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D007378:Interleukins / Q000276:immunology / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D009369:Neoplasms; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D000097043:Interleukin-22
chemical_list: D019138:Antibodies, Blocking; D004268:DNA-Binding Proteins; D007378:Interleukins; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D000097043:Interleukin-22; C499308:Rag2 protein, mouse