IFN-gamma-inducing factor; Igif; IL-1 gamma; IL-18; Il18; Interferon gamma-inducing factor; interferon-gamma-inducing factor; Interleukin-1 gamma; Interleukin-18

Interleukin-18 (IL-18), also known as IL-1F4 and IFN-gamma inducing factor (IGIF), is a member of the IL-1 family of cytokines and is a key molecule in the innate immune response. Rat IL-18 is synthesized as a 24 kDa proprotein that contains a 36 amino acid (aa) propeptide and a 158 aa mature region. Under inflammatory conditions, the propeptide is cleaved by Caspase-1 in the cytoplasm to liberate the mature nonglycosylated 18 kDa monomeric IL-18. Mature rat IL-18 shares 91% aa sequence identity with mouse IL-18 and 60-64% aa sequence identity with human, canine, feline, porcine, and rhesus macaque IL-18. IL-18 is secreted by a variety of cell types including macrophages, dendritic cells, and epithelial cells. Circulating mature IL-18 is sequestered by soluble IL-18 binding proteins (IL-18 BP) that inhibit IL-18 bioactivity. IL-18 interacts with the widely expressed IL-18 R alpha which then recruits the signaling subunit IL-18 R beta. The IL-1 family member IL-1F7 also binds to IL-18 R alpha but does not recruit IL-18 R beta or induce signaling. IL-1F7 binds IL-18 BP and enhances its neutralizing effect on IL-18 activity. IL-18 synergizes with other cytokines to activate NK, Th1, and Th17 cells and to increase the production of IFN-gamma. IL-18 can also promote Th2 cytokine release which reduces the effectiveness of antiviral responses. Increased levels of active IL-18 contribute to the severity of autoimmunity and hypertension, while deficiency of IL-18 results in symptoms of metabolic syndrome. In cancer, IL-18 stimulates Th1 and NK cells to target tumor cells, but it can also promote angiogenesis, metastasis, and tumor cell immune evasion.