Tumor necrosis factor-alpha is a potent endogenous mutagen that promotes cellular transformation.
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.
Yan
Bin
B
Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina, USA.
Wang
Huili
H
Rabbani
Zahid N
ZN
Zhao
Yulin
Y
Li
Wenrong
W
Yuan
Yuqing
Y
Li
Fang
F
Dewhirst
Mark W
MW
Li
Chuan-Yuan
CY
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*
D005452:Fluoresceins; D009153:Mutagens; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; C029569:diacetyldichlorofluorescein; D003571:Cytochalasin B