Role of the MAPK pathway in the observed bystander effect in lymphocytes co-cultured with macrophages irradiated with γ-rays or carbon ions.
OBJECTIVE
The radiation-induced bystander effect (RIBE) has potential implications in cancer risks from space particle radiation; however, the mechanisms underlying RIBE are unclear. The role of the MAPK pathway in the RIBEs of different linear energy transfer (LET) was investigated.


METHODS
Human macrophage U937 cells were irradiated with γ-rays or carbon ions and then co-cultured with nonirradiated HMy2.CIR (HMy) lymphocytes for different periods. The activation of MAPK proteins and the generation of intracellular nitric oxide (NO) and reactive oxygen species (ROS) in the irradiated U937 cells were measured. Micronuclei (MN) formation in the HMy cells was applied to evaluate the bystander damage. Some U937 cells were pretreated with different MAPK inhibitors before irradiation.


RESULTS
Additional MN formation was induced in the HMy cells after co-culturing with irradiated U937 cells, and the yield of this bystander MN formation was dependent on the co-culture period with γ-ray irradiation but remained high after 1h of co-culture with carbon irradiation. Further investigations disclosed that the time response of the RIBEs had a relationship with LET, where ERK played a different role from JNK and p38 in regulating RIBEs by regulating the generation of the bystander signaling factors NO and ROS.


CONCLUSIONS
The finding that the RIBE of high-LET radiation could persist for a much longer period than that of γ-rays implies that particle radiation during space flight could have a high risk of long-term harmful effects. An appropriate intervention targeting the MAPK pathway may have significant implications in reducing this risk.
Institute of Radiation Medicine, Fudan University, No. 2094 Xie-Tu Road, Shanghai 200032, China.
Chen
C
Dong
Institute of Radiation Medicine, Fudan University, No. 2094 Xie-Tu Road, Shanghai 200032, China.
Mingyuan
M
He
Institute of Radiation Medicine, Fudan University, No. 2094 Xie-Tu Road, Shanghai 200032, China.
Ruiping
R
Ren
Institute of Radiation Medicine, Fudan University, No. 2094 Xie-Tu Road, Shanghai 200032, China.
Yuexia
Y
Xie
Institute of Radiation Medicine, Fudan University, No. 2094 Xie-Tu Road, Shanghai 200032, China.
Dexiao
D
Yuan
Institute of Modern Physics, Chinese Academy of Sciences, No. 509 Nanchang Road, Lanzhou 730000, China.
Bingrong
B
Dang
Institute of Modern Physics, Chinese Academy of Sciences, No. 509 Nanchang Road, Lanzhou 730000, China.
Wenjian
W
Li
Institute of Radiation Medicine, Fudan University, No. 2094 Xie-Tu Road, Shanghai 200032, China. Electronic address: clshao@shmu.edu.cn.
Chunlin
C
Shao
D024201:Bystander Effect / Q000528:radiation effects*; D002250:Carbon Radioisotopes; D018920:Coculture Techniques; D004307:Dose-Response Relationship, Radiation; D005720:Gamma Rays; D006801:Humans; D008214:Lymphocytes / Q000528:radiation effects*; D020935:MAP Kinase Signaling System / Q000528:radiation effects*; D008264:Macrophages / Q000528:radiation effects*; D015162:Micronucleus Tests; D009569:Nitric Oxide / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D020298:U937 Cells
D002250:Carbon Radioisotopes; D017382:Reactive Oxygen Species; D009569:Nitric Oxide
Bystander effect; LET-dependent; MAPK pathways; Radiation