Investigation of the mechanisms underpinning IL-6 cytokine release in bystander responses: the roles of radiation dose, radiation quality and specific ROS/RNS scavengers.
OBJECTIVE
To investigate the mechanisms regulating the pathways of the bystander transmission in vitro, focusing on the radiation-perturbed signalling (via Interleukine 6, IL-6) of the irradiated cells after exposure to low doses of different radiation types.


METHODS
An integrated 'systems radiation biology' approach was adopted. Experimentally the level of the secreted cytokine from human fibroblasts was detected with ELISA (Enzyme-Linked ImmunoSorbent Assay) method and subsequently the data were analyzed and coupled with a phenomenological model based on differential equations to evaluate the single-cell release mechanisms.


RESULTS
The data confirmed the important effect of radiation on the IL-6 pathway, clearly showing a crucial role of the ROS (Reactive Oxygen Species) in transducing the effect of initial radiation exposure and the subsequent long-term release of IL-6. Furthermore, a systematic investigation of radiation dose/radiation quality dependence seems to indicate an increasing efficiency of high LET (Linear Energy Transfer) irradiation in the release of the cytokine. Basic hypotheses were tested, on the correlation between direct radiobiological damage and signal release and on the radiation target for this endpoint (secretion of IL-6).


CONCLUSIONS
The results demonstrate the role of reactive oxygen and nitrogen species in the signaling pathways of IL-6. Furthermore the systems radiation biology approach here adopted, allowed us to test and verify hypotheses on the behavior of the single cell in the release of cytokine, after the exposure to different doses and different qualities of ionizing radiation.
Department of Physics, University of Pavia, Pavia, and Istituto Nazionale di Fisica Nucleare, Sezione di Pavia, Italy. luca.mariotti@oncology.ox.ac.uk
Luca G
LG
Mariotti
Alessia
A
Bertolotti
Elena
E
Ranza
Gabriele
G
Babini
Andrea
A
Ottolenghi
D024201:Bystander Effect / Q000187:drug effects* / Q000528:radiation effects*; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D003497:Cyclic N-Oxides / Q000494:pharmacology / Q000633:toxicity; D004121:Dimethyl Sulfoxide / Q000494:pharmacology / Q000633:toxicity; D004307:Dose-Response Relationship, Radiation; D016166:Free Radical Scavengers / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology / Q000633:toxicity; D015850:Interleukin-6 / Q000378:metabolism*; D018499:Linear Energy Transfer / Q000187:drug effects; D008954:Models, Biological; D026361:Reactive Nitrogen Species / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D049490:Systems Biology; D013997:Time Factors
D003497:Cyclic N-Oxides; D016166:Free Radical Scavengers; D007093:Imidazoles; D015850:Interleukin-6; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; C079391:2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide; D004121:Dimethyl Sulfoxide