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.

Nonhuman primates as models for the discovery and development of radiation countermeasures

“…Among these proteins are IL-6, C-reactive protein (CRP), serum amyloid A (SAA), growth arrest and DNA damage-inducible 45 (GADD45) proteins, FMS-like tyrosine kinase 3 ligand (FLT3L), and salivary α-amylase. Recently, IL-18 has been reported as a biomarker for radiation injury [111–113]. We evaluated serum samples for IL-18 collected from a large number of NHPs exposed to three different doses of radiation (5.8, 6.5, and 7.2 Gy) at various time points after exposure, though serum from irradiated animals had higher levels of IL-18, it showed no specific correlation with radiation dose and time course [98].…”

IL-33 signaling contributes to the pathogenesis of myeloproliferative neoplasms

“…These results suggest that JAK2 Figure 2A, and Figure 1C). Accordingly, the irradiation-induced increase in proinflammatory cytokines such as IL-6 and G-CSF, but also IL-33 (35,36), likely accounts for the accelerated disease kinetics observed in chimeric mice reconstituted with styx BM compared with nonmanipulated styx mutants (Figures 1 and 3). Irradiation-induced systemic inflammation may also mask the relative contribution of radio-resistant cells to MPN-like disease in our model.…”

The Role of IL-33-Dependent Inflammation in the Tumor Microenvironment

“…Moreover, no information was provided on the therapeutic status of the analyzed patient samples. Indeed, radiotherapy, alone or in combination with chemotherapy, belongs to the standard treatment of NSCLC (45), which can lead to a rapid increase in the expression of IL-33 protein in tissues (46). Thus, careful evaluation of patient therapeutic history is key for the study of IL-33 signaling in human samples.…”