title: Circulating IL-18 Binding Protein (IL-18BP) and IL-18 as Dual Biomarkers of Total-Body Irradiation in Mice.
abstract: We have previously reported that circulating interleukin-18 (IL-18) can be used as a radiation biomarker in mice, minipigs and nonhuman primates. In this study, we further determined the serum levels of IL-18 binding protein (IL-18BP), a natural endogenous antagonist of IL-18, in CD2F1 mice 1-13 days after total-body gamma irradiation (TBI) with different doses (5-10 Gy). We compared the changes in blood lymphocyte, neutrophil and platelet counts as well as the activation of the proapoptotic executioner caspase-3 and caspase-7, and the expression of the inflammatory factor cyclooxygenase 2 (COX-2) in spleen cells, with the changes of IL-18BP and IL-18 in mouse serum. We also evaluated the significance, sensitivity and specificity of alterations in radiation-induced IL-18BP. IL-18 increased from day 1-13 after TBI in a dose-dependent manner that was paralleled with an increase in IL-18 receptor alpha (IL-18Rα) in irradiated mouse spleen cells. IL-18BP rapidly increased (25-63 fold) in mouse serum on day 1 after different doses of TBI. However, it returned to baseline within 3 days after 5-7 Gy doses and within 7 days after 8 Gy dose, and was unaltered thereafter. In contrast, high doses of radiation (9 and 10 Gy) significantly sustained a higher level of IL-18BP in mouse serum and later induced a second phase of increase in IL-18BP on day 9-13 after irradiation, which coincided with the onset of animal mortality. Consistent with this observation, highly activated caspase-3 and -7 in 8-10 Gy irradiated mouse spleen cells exhibited reduced or no activity 24 h after 5 Gy, although radiation induced an inflammatory response, as shown by COX-2 expression in all irradiated cells. Our data suggest that the radiation-induced differential elevation of IL-18 and IL-18BP in animal serum is a dynamic and discriminative indicator of the severity of injury after exposure to ionizing radiation. These findings support the inclusion of the dual biomarkers IL-18BP and IL-18 in the development of a multifactorial strategy for radiation dose and injury assessment.
authors.affiliation: Radiation Countermeasures Program, Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, Maryland.
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.
authors.forename: XiangHong
authors.initials: X
authors.lastname: Li
authors.affiliation: Radiation Countermeasures Program, Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, Maryland.
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.
authors.forename: Mang
authors.initials: M
authors.lastname: Xiao
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D003037:Cobalt Radioisotopes / Q000009:adverse effects; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004307:Dose-Response Relationship, Radiation; D004789:Enzyme Activation / Q000528:radiation effects; D015971:Gene Expression Regulation, Enzymologic / Q000528:radiation effects; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood* / Q000378:metabolism; D020382:Interleukin-18 / Q000097:blood* / Q000378:metabolism; D018655:Lymphocyte Count; D008297:Male; D051379:Mice; D009504:Neutrophils / Q000166:cytology / Q000528:radiation effects; D011832:Radiation Injuries / Q000097:blood / Q000209:etiology; D013154:Spleen / Q000378:metabolism / Q000528:radiation effects; D016019:Survival Analysis; D013997:Time Factors; D014916:Whole-Body Irradiation / Q000009:adverse effects*
chemical_list: D015415:Biomarkers; D003037:Cobalt Radioisotopes; D036341:Intercellular Signaling Peptides and Proteins; D020382:Interleukin-18; C118370:interleukin-18 binding protein; D051546:Cyclooxygenase 2; D053148:Caspase 3; D053179:Caspase 7