title: Circulating interleukin-18 as a biomarker of total-body radiation exposure in mice, minipigs, and nonhuman primates (NHP).
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.
authors.affiliation: Radiation Countermeasures Program, Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, Maryland, United States of America.
authors.forename: Cam T
authors.initials: CT
authors.lastname: Ha
authors.affiliation: Radiation Countermeasures Program, Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, Maryland, United States of America.
authors.forename: Xiang-Hong
authors.initials: XH
authors.lastname: Li
authors.affiliation: Radiation Countermeasures Program, Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, Maryland, United States of America.
authors.forename: Dadin
authors.initials: D
authors.lastname: Fu
authors.affiliation: Radiation Countermeasures Program, Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, Maryland, United States of America.
authors.forename: Maria
authors.initials: M
authors.lastname: Moroni
authors.affiliation: Radiation Countermeasures Program, Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, Maryland, United States of America.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Fisher
authors.affiliation: Radiation Countermeasures Program, Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, Maryland, United States of America.
authors.forename: Robert
authors.initials: R
authors.lastname: Arnott
authors.affiliation: Radiation Countermeasures Program, Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, Maryland, United States of America.
authors.forename: Venkataraman
authors.initials: V
authors.lastname: Srinivasan
authors.affiliation: Radiation Countermeasures Program, Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, Maryland, United States of America.
authors.forename: Mang
authors.initials: M
authors.lastname: Xiao
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D016207:Cytokines / Q000097:blood / Q000235:genetics / Q000378:metabolism; D005260:Female; D005720:Gamma Rays; D005786:Gene Expression Regulation / Q000528:radiation effects; D020382:Interleukin-18 / Q000097:blood* / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D009928:Organ Specificity; D011323:Primates; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013552:Swine; D014916:Whole-Body Irradiation
chemical_list: D015415:Biomarkers; D016207:Cytokines; D020382:Interleukin-18