Non-linear response of cells to signals leads to revised characteristics of bystander effects inferred from their modelling.
OBJECTIVE
To analyze the response of naïve cells to bystander signals, thus complementing previous studies on signal emission by irradiated cells and improving quantitative understanding of bystander effects.


METHODS
Published data on reduced clonogenic survival and mutation induction in bystander experiments with undiluted and diluted irradiated cell-conditioned medium were analyzed using linear and non-linear response functions.


RESULTS
The data indicated a highly non-linear response of cells to bystander signals. It can be described with sigmoid response functions, involving only a single additional parameter compared to the linear response assumed in existing models. Accounting for this non-linearity significantly modifies bystander characteristics inferred from the modelling, such as signal lifetime or dose dependence of signal release. Some signal release models are even ruled out.


CONCLUSIONS
The sigmoid response to signals reflects complex intracellular pathways triggered and, together with the non-linear release of signals, supports the involvement of cytokines and/or reactive oxygen species in bystander effects. Further research combining experimental and modelling approaches is needed to elucidate the mechanisms of intercellular communication and their modifications by radiation, in particular to determine the nature of bystander signals, dynamics of their release after irradiation, and cellular responses to these signals.
Helmholtz Zentrum München, Institute of Radiation Protection, Neuherberg, Germany. pavel.kundrat@helmholtz-muenchen.de
Pavel
P
Kundrát
Werner
W
Friedland
D024201:Bystander Effect / Q000528:radiation effects*; D002460:Cell Line; D019295:Computational Biology; D017077:Culture Media, Conditioned / Q000528:radiation effects; D006801:Humans; D008954:Models, Biological; D009154:Mutation / Q000528:radiation effects; D017711:Nonlinear Dynamics; D015398:Signal Transduction / Q000528:radiation effects*; D013937:Thymidine Kinase / Q000235:genetics
D017077:Culture Media, Conditioned; D013937:Thymidine Kinase