Abstract
We aim to develop a rapid, easy-to-use, inexpensive and accurate radiation dose-assessment assay that tests easily obtained samples (e.g., blood) to triage and track radiological casualties, and to evaluate the radioprotective and therapeutic effects of radiation countermeasures. In the present study, we evaluated the interleukin (IL)-1 family of cytokines, IL-1β, IL-18 and IL-33, as well as their secondary cytokines’ expression and secretion in CD2F1 mouse bone marrow (BM), spleen, thymus and serum in response to γ-radiation from sublethal to lethal doses (5, 7, 8, 9, 10, or 12 Gy) at different time points using the enzyme-linked immune sorbent assay (ELISA), immunoblotting, and cytokine antibody array. Our data identified increases of IL-1β, IL-18, and/or IL-33 in mouse thymus, spleen and BM cells after total-body irradiation (TBI). However, levels of these cytokines varied in different tissues. Interestingly, IL-18 but not IL-1β or IL-33 increased significantly (2.5–24 fold) and stably in mouse serum from day 1 after TBI up to 13 days in a radiation dose-dependent manner. We further confirmed our finding in total-body γ-irradiated nonhuman primates (NHPs) and minipigs, and demonstrated that radiation significantly enhanced IL-18 in serum from NHPs 2–4 days post-irradiation and in minipig plasma 1–3 days post-irradiation. Finally, we compared circulating IL-18 with the well known hematological radiation biomarkers lymphocyte and neutrophil counts in blood of mouse, minipigs and NHPs and demonstrated close correlations between these biomarkers in response to radiation. Our results suggest that the elevated levels of circulating IL-18 after radiation proportionally reflect radiation dose and severity of radiation injury and may be used both as a potential biomarker for triage and also to track casualties after radiological accidents as well as for therapeutic radiation exposure.
Highlights
Radiation injuries are heterogeneous disorders that involve many pathophysiological pathways and affect both cells directly exposed to radiation and cells not directly exposed
Results in figure 1A showed that 8 and 1.5-fold (8 Gy) and 2-fold (10 Gy) radiation induced about 4-fold increases of IL-1b and IL-33 in thymi 1 day after irradiation compared to shamirradiated control
We examined the effects of c-radiation on three IL-1 family cytokines, IL-1b, IL-18, and IL-33
Summary
Radiation injuries are heterogeneous disorders that involve many pathophysiological pathways and affect both cells directly exposed to radiation and cells not directly exposed. Total-body 60Co c-radiation induced 90% mortality within 30 days (LD90/30) with a 95% confidence interval (CI) at doses of 9.6 Gy in CD2F1 mice [6], 1.86 Gy in Gottingen minipigs [7] and 7.56 Gy in rhesus macaques (LD90/60 without supportive care) [8], showing that the radiation sensitivity in various animal species differs significantly The mechanisms of these complex biological responses of tissues to harmful radiation damage are not well understood, and rapid, easy-to-use, inexpensive and accurate methods for assessing radiation doses and evaluating radiationinduced injury as well as the effects of radiation countermeasures are not available, multiple parameter biomarkers have been reported [9,10,11]. The present study provides a novel method for determining radiation injury by quantitation of circulating IL-18 in different animal species using ELISA (enzyme-linked immune sorbent assay)
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