IL-18 binding protein (IL-18BP) as a novel radiation countermeasure after radiation exposure in mice

Abstract

Recent studies suggested that radiation exposure causes local and systemic inflammatory responses and induces cell and tissue damage. We have reported that IL-18 plays an important role in radiation-induced injury. Here, we demonstrate that IL-18 binding protein (IL-18BP), a natural antagonist of IL-18, was significantly increased (1.7–63 fold) in mouse serum on day 1 after 0.5–10 Gy TBI. However, this high level of IL-18BP was not sufficient to neutralize the active IL-18 in irradiated mice, resulting in a radiation dose-dependent free IL-18 increase in these mice’s serum which led to pathological alterations to the irradiated cells and tissues and finally caused animal death. Administration of recombinant human (rh) IL-18BP (1.5 mg/kg) with single (24, 48 or 72 h post-TBI) or double doses (48 h and 5 days post-TBI) subcutaneous (SC) injection increased 30-day survival of CD2F1 mice after 9 Gy TBI 12.5–25% compared with the vehicle control treated group, respectively. Furthermore, the mitigative effects of rhIL-18BP included balancing the ratio of IL-18/IL-18BP and decreasing the free IL-18 levels in irradiated mouse serum and significantly increasing blood cell counts, BM hematopoietic cellularity and stem and progenitor cell clonogenicity in mouse BM. Furthermore, IL-18BP treatment inhibited the IL-18 downstream target interferon (IFN)-γ expression in mouse BM, decreased reactive oxygen species (ROS) level in the irradiated mouse heart tissues, attenuated the stress responsive factor GDF-15 (growth differentiation factor-15) and increased the intestine protector citrulline level in total body irradiated mouse serum, implicating that IL-18BP may protect multiple organs from radiation-induced inflammation and oxidative stress. Our data suggest that IL-18 plays a key role in radiation-induced cell and tissue damage and dysfunction; and for the first time demonstrated that IL-18BP counters IL-18 activation and therefore may mitigate/treat radiation-induced multiple organ injuries and increase animal survival with a wider therapeutic window from 24 h and beyond after lethal doses of radiation exposure.

Interleukin-18 cytokine in immunity, inflammation, and autoimmunity: Biological role in induction, regulation, and treatment

“…IL-18 binding protein (IL-18BP) is a natural antagonist of IL-18, belonging to the immunoglobulin like receptor type but is not cleaved on cell surface ( 221 ). It is a naturally occurring 18 binding agent was first identified in 1999.…”

CDX-301 prevents radiation-induced dysregulation of miRNA expression and biogenesis

“…Circulating IL-18 has been shown to be a biomarker of exposure to TBI in three animal models, namely mice, minipigs, and non-human primates. 71 , 72 Administration of human rIL-17B has been shown to promote neutrophil migration in healthy mice. 73 Moreover, IL-17 family members induce inflammatory cytokines not only through activated T cells but also through activated monocytes/macrophages, which are the primary cells in the bone marrow that are damaged by exposure to radiation.…”

Dengue Infection - Recent Advances in Disease Pathogenesis in the Era of COVID-19

“…In a more recent study, Li et al (2020) used recombinant human IL-18 (rhIL-18BP) to decrease soluble IL-18 in irradiated experimental mouse. The administration of IL-18BP was found to inhibit the down-stream activities of IL-18, and the treated mouse showed low levels of IFN-g, reactive oxygen species (ROS) as well as attenuated a stress responsive factor named growth differentiation factor-15 (GDF-15) (132). The study was encouraging as it showed that IL-18 played a paramount role in radiation-induced tissue damage and treatment with IL-18BP likely mitigates tissue injury/ damage induced by radiation.…”