Radiation-Induced Delayed Bystander-Type Effects Mediated by Hemopoietic Cells

Abstract

Genetic lesions and cell death associated with exposure to ionizing radiation have generally been attributed to DNA damage arising as a consequence of deposition of energy in the cell nucleus. However, reports of radiation-induced bystander effects, in which DNA damage is produced in nonirradiated cells as a consequence of communication with irradiated cells, indicate additional mechanisms. At present, most information has been obtained using in vitro systems, and the in vivo significance of bystander factors is not clear. In this study we show that signals generated in vivo in the bone marrow of CBA/Ca mice irradiated with 4 Gy gamma rays 24 h previously, but not immediately postirradiation, are able to induce DNA damage and apoptosis in nonirradiated bone marrow cells. The signaling mechanism involves FasL, TNF-alpha, nitric oxide and superoxide and macrophages are implicated as a source of damaging signals. Such delayed bystander-type damage demonstrates the importance of studying tissue responses subsequent to the radiation exposure as well as effects at the time of irradiation when considering the mechanisms underlying the consequences of radiation exposures.

TNF-TNFR2/p75 Signaling Inhibits Early and Increases Delayed Nontargeted Effects in Bone Marrow-derived Endothelial Progenitor Cells

“…The experiment showed an increasing trend in the number of sub-G 0 cells at the 1-, 2-, and 3-h time points post-irradiation. When TNF-␣ neutralizing antibody was added to the irradiated bone marrow medium, the number of sub-G 0 cells was significantly decreased in all three time points (24,90). Reduction was also noted for Fas ligand neutralizing antibody, which might be another signal of interest.…”

“…Hematopoietic EPCs originate from the bone marrow and are part of the subpopulation of hematopoietic stem cells, which have been shown to be sensitive to radiobiological bystander response (20,24,70). EPCs are recruited to areas of neovascularization in the process of vasculogenesis to repair tissues with ischemia and cardiovascular diseases (44,48,57).…”

“…This is mediated by a release of various cytokines, superoxide, and nitric oxide (8). All of which are capable of causing tissue damage (22) by signaling through pro-apoptosis mediator TNF-␣, Fas ligand, nitric oxide, and superoxide (23,24).…”

“…IL-8 expression is under the control of ciselements of nuclear factor NF-B, which is associated with the major pro-inflammatory pathway for TNF-␣ (89). TNF-␣ was also directly implicated as one of the damaging signals in in vivo bystander experiments, as well as Fas ligand, nitric oxide, and super oxide (24,90). Hematopoietic cells from bone marrow were treated with radiation and measured for cells in sub-G 0 region as a screening method for dead/damaged cells.…”

The effect of genetic background and dose on non-targeted effects of radiation

“…Cytokines are involved in a range of cellular regulating pathways, and it is known that tumor necrosis factor-α (TNF-α) and transforming growth factor-β (TGF-β) levels are reported to change in response to irradiation (Facoetti et al 2006, Lorimore et al 2008, Burr et al 2010. TNF-α is involved in inflammatory responses, activating nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB), mitogen-activated protein kinases (MAPK) pathways and apoptotic pathways.…”