Genomic Maintenance & Repair

Monday, October 17, 2005 3:00 PM-5:00 PM Exhibit Hall

(PP304) TNF as a potential signaling mediator of genomic instability and the bystander effect.

Gibbons, Catherine*,1, 2, Natarajan, Mohan3, Mohan, Sumathy4, Pandeswara, S3, Moore, Stephen1, Grosovsky, Andrew2, Kadhim, Munira1, 1 Radiation and Genome Stability Unit, Harwell, Oxfordshire, UK2 Environmental Toxicology Graduate Program, Riverside, CA, USA3 Department of Radiation Oncology, San Antonio, TX, USA4 Department of Pathology, San Antonio, TX, USA

ABSTRACT- Genomic instability has been demonstrated in the progeny of irradiated cells and unirradiated bystander cells. Bystander responses are thought to depend on the activation of cellular communication processes. In this study we examine one such mediator of cellular communication, the pro-inflammatory cytokine tumor necrosis factor alpha (TNF). Previous studies have shown that low doses of ionizing radiation are sufficient to transiently activate the DNA binding specificity of transcription factor NF-B, perhaps mediated by reactive oxygen intermediates (ROIs). TNF is a potent activator of NF-B, and its expression is also known to increase following exposure to low radiation doses. We hypothesize that low dose activation of NF-B up-regulates TNF expression in irradiated cells. The secreted TNF might then further stimulate the activation of NF-B in both the irradiated cell and unirradiated bystander cells, thus increasing TNF expression. Such a feedback cycle could be involved in the bystander effects of radiation exposure (via ROIs), as well as delayed effects (via TNF/NF-B signaling). In order to investigate this hypothesis, human aortic endothelial cell cultures were incubated with TNF. Cells exposed to 0.1 and 2 Gy X-rays were used as positive controls. DNA damage was assessed immediately using the comet assay, and genomic instability was measured by delayed chromosomal aberrations. We observed an increase in chromosomal instability in cultures treated with TNF. However, there was no detectable increase in DNA damage immediately following exposure as measured by the comet assay, nor was there any effect on cell survival. These results indicate that TNF is capable of generating chromosomal instability in cells that have not been irradiated. We anticipate that instability may also be induced in bystander cells and studies are underway to examine this possibility.

Key words: genomic instability, bystander effect, cytokines, TNF

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2005 RRS