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Exposure to ionizing radiation is a crucial life-threatening factor in nuclear and radiological incidents. It is known that ionizing radiation affects cytokine/chemokine concentrations in the blood of B6D2F1 mice. It is not clear whether radiation dose rates would vary the physiological response. Therefore, in this study we utilized data from two experiments using B6D2F1 female mice exposed to six different dose rates ranging from low to high rates. In one experiment, mice received a total dose of 8 Gy (LD 0/30 ) of 60 Co gamma radiation at four dose rates: 0.04, 0.15, 0.30 and 0.47 Gy/min. Blood samples from mice were collected at 24 and 48 h postirradiation for cytokine/chemokine measurements, including interleukin (IL)-1β, IL-6, IL-10, keratinocyte cytokine (KC), IL-12p70, IL-15, IL-17A, IL-18, granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage (GM)-CSF, macrophage (M)-CSF, monokine induced by gamma interferon (MIG), tumor necrosis factor (TNF)-α, fibroblast growth factor (FGF)-basic, vascular endothelial growth factor (VEGF) and platelet-derived growth factor basic (PDGF-bb). At 24 h after ionizing irradiation at dose rate of 0.04 Gy/min, significant increases were observed only in G-CSF and M-CSF ( P < 0.05). At 0.15 Gy/min, IL-10, IL-17A, G-CSF and GM-CSF concentrations were increased. At 0.3 Gy/min, IL-15, IL-18, G-CSF, GM-CSF, M-CSF, MCP-1, MIP-2, MIG, FGF-basic, VEGF and PDGF-bb were significantly elevated ( P < 0.05). At 0.47 Gy/min, IL-6, KC, IL-10, MCP-1, G-CSF, GM-CSF and M-CSF were significantly increased. At 48 h postirradiation, all cytokines/chemokines except MCP-1 returned to or were below their baselines, suggesting these increases are transient at LD 0/30 irradiation. Of note, there is a limitation on day 2 because cytokines/chemokines are either at or below their baselines. Other parameters such as fms-like tyrosine kinase receptor-3 ligand (Flt-3 ligand) concentrations and lymphocyte counts, which have proven to be unaffected by radiation dose rates, can be used instead for assessing the radiation dose. However, in a separate radiation dose and time-course experiment, increases in IL-18 and G-CSF depended on the radiation doses but showed no significant differences between 0.58 and 1.94 Gy/min ( P > 0.05) at 3 and 6 Gy but not 12 Gy. G-CSF continued to increase up to day 7, whereas IL-18 increased on day 4 and remained above baseline level on day 7. Therefore, time after irradiation at different doses should be taken into consideration. To our knowledge, these results are the first to suggest that ionizing radiation, even at a very low-dose-rate (0.04 Gy/min), induces circulating G-CSF increases but not others for selected time points; radiation-induced increases in IL-18 at radiation dose rates between 0.15 and 1.94 Gy/min are also not in a radiation dose-rate-dependent manner. C-CSF, lymphocyte counts and circulating Flt-3 ligand should be explored further as possible biomarkers of radiation exposure at early time points. IL-18 is also worthy of further study as a potential biomarker at later time points.

We have reported that circulating IL-18 can be used as a radiation biomarker in mice, minipigs and nonhuman primates (NHPs, Macaca mulatta). Here, we report the levels of IL-18 in individual NHP's urine before and at 6 h-7 days after 5.0, 6.5 and 8.5 Gy 60 Co total-body irradiation (TBI) using enzyme linked immunosorbent assay (ELISA). Six animals (3.5-5.5 kg, 3-4 years old) per radiation dose were investigated. Correlation values between urine IL-18 and blood cell counts and serum chemistry parameters including lactate dehydrogenase (LDH), lipase, and serum total protein (TP), as well as between urine IL-18 and 60-day survival, were analyzed. Our data, to the best of our knowledge, for the first time, demonstrate that concentrations of urine IL-18 from irradiated NHPs were increased in a radiation dose-dependent manner compared to pre-TBI levels in samples from these animal (N = 18, 11.02 ± 1.3 pg/ml). A 5.0 Gy low dose of radiation (∼LD 10/60 ) did not increase urine IL-18 levels. In contrast, high-dose TBI significantly increased urine IL-18 at day 1 to day 5 in a bell-shaped time course, reaching a peak of 5- to 10-fold of control levels on day 3 after 6.5 Gy (∼LD 50/60 ) and 8.5 Gy (∼LD 90/60 ), respectively. Statistical analysis using receiver operator characteristic (ROC) and MultiROC analysis indicated that white blood cell and platelet counts, serum LDH, lipase and TP, when combined with urine IL-18, provide discriminatory predictors of total-body radiation injury with a very high ROC area of 0.98. Urine IL-18 measurement, as an early prognostic indicator of survival, may facilitate rapid detection of lethal doses of radiation, based on the currently available data set.