Mechanism of radiation-induced bystander effects: a unifying model.
The radiation-induced bystander effect represents a paradigm shift in our understanding of the radiobiological effects of ionizing radiation, in that extranuclear and extracellular events may also contribute to the final biological consequences of exposure to low doses of radiation. Although radiation-induced bystander effects have been well documented in a variety of biological systems, the mechanism is not known. It is likely that multiple pathways are involved in the bystander phenomenon, and different cell types respond differently to bystander signalling. Using cDNA microarrays, a number of cellular signalling genes, including cyclooxygenase-2 (COX-2), have been shown to be causally linked to the bystander phenomenon. The observation that inhibition of the phosphorylation of extracellular signal-related kinase (ERK) suppressed the bystander response further confirmed the important role of the mitogen-activated protein kinase (MAPK) signalling cascade in the bystander process. Furthermore, cells deficient in mitochondrial DNA showed a significantly reduced response to bystander signalling, suggesting a functional role of mitochondria in the signalling process. Inhibitors of nitric oxide (NO) synthase (NOS) and mitochondrial calcium uptake provided evidence that NO and calcium signalling are part of the signalling cascade. The bystander observations imply that the relevant target for various radiobiological endpoints is larger than an individual cell. A better understanding of the cellular and molecular mechanisms of the bystander phenomenon, together with evidence of their occurrence in-vivo, will allow us to formulate a more accurate model for assessing the health effects of low doses of ionizing radiation.
Hei
Tom K
TK
Center for Radiological Research, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA. tkh1@columbia.edu
Zhou
Hongning
H
Ivanov
Vladimir N
VN
Hong
Mei
M
Lieberman
Howard B
HB
Brenner
David J
DJ
Amundson
Sally A
SA
Geard
Charles R
CR
D000818:Animals; D024201:Bystander Effect; D002478:Cells, Cultured; D018031:Connexin 43 / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004247:DNA / Q000528:radiation effects*; D004272:DNA, Mitochondrial / Q000378:metabolism; D004307:Dose-Response Relationship, Radiation; D017629:Gap Junctions / Q000378:metabolism / Q000528:radiation effects*; D006801:Humans; D008928:Mitochondria / Q000378:metabolism / Q000528:radiation effects; D008954:Models, Biological; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D011829:Radiation Dosage; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000528:radiation effects*
D018031:Connexin 43; D017077:Culture Media, Conditioned; D016207:Cytokines; D004272:DNA, Mitochondrial; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D004247:DNA; D051546:Cyclooxygenase 2