title: Tumor necrosis factor-alpha is a potent endogenous mutagen that promotes cellular transformation.
abstract: Tumor necrosis factor-alpha (TNF-alpha) is an important inflammation cytokine without known direct effect on DNA. In this study, we found that TNF-alpha can cause DNA damages through reactive oxygen species. The mutagenic effect of TNF-alpha is comparable with that of ionizing radiation. TNF-alpha treatment in cultured cells resulted in increased gene mutations, gene amplification, micronuclei formation, and chromosomal instability. Antioxidants significantly reduced TNF-alpha-induced genetic damage. TNF-alpha also induced oxidative stress and nucleotide damages in mouse tissues in vivo. Moreover, TNF-alpha treatment alone led to increased malignant transformation of mouse embryo fibroblasts, which could be partially suppressed by antioxidants. As TNF-alpha is involved in chronic inflammatory diseases, such as chronic hepatitis, ulcerative colitis, and chronic skin ulcers, and these diseases predispose the patients to cancer development, our results suggest a novel pathway through which TNF-alpha promotes cancer development through induction of gene mutations, in addition to the previously reported mechanisms, in which nuclear factor-kappaB activation was implicated.
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Yan
authors.forename: Huili
authors.initials: H
authors.lastname: Wang
authors.forename: Zahid N
authors.initials: ZN
authors.lastname: Rabbani
authors.forename: Yulin
authors.initials: Y
authors.lastname: Zhao
authors.forename: Wenrong
authors.initials: W
authors.lastname: Li
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Yuan
authors.forename: Fang
authors.initials: F
authors.lastname: Li
authors.forename: Mark W
authors.initials: MW
authors.lastname: Dewhirst
authors.forename: Chuan-Yuan
authors.initials: CY
authors.lastname: Li
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D003110:Colonic Neoplasms; D003571:Cytochalasin B / Q000494:pharmacology; D004249:DNA Damage; D005452:Fluoresceins; D005784:Gene Amplification; D006801:Humans; D051379:Mice; D009153:Mutagens; D009154:Mutation; D018384:Oxidative Stress / Q000187:drug effects; D010957:Plasmids; D017382:Reactive Oxygen Species / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000494:pharmacology*
chemical_list: D005452:Fluoresceins; D009153:Mutagens; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; C029569:diacetyldichlorofluorescein; D003571:Cytochalasin B