Interleukin-18 (IL 18) is a member of the IL 1 family of cytokines. Increasing reports have expanded the role of IL 18 in mediating inflammation in animal models of disease using IL 18 deficient mice, neutralization of IL 18 or deficiency in the IL 18 receptor alpha chain. Similar to IL 1β, IL 18 is synthesized as an inactive precursor requiering processing by caspase 1 into an active cytokine but unlike IL 1β, the IL 18 precursor is constitutively present in nearly all cells in healthy humans and animals. The activity of IL 18 is balanced by the presence of a high-affinity naturally occuring IL 18 binding protein (IL 18BP). In humans, disease increased disease severity can be associated with an imbalance of IL 18 to IL 18BP such that the levels of free IL 18 are elevated in the circulation. A role for IL 18 has been implicated in several autoimmune diseases, myocardial function, emphysema, metabolic syndromes, psoriasis, inflammatory bowel disease, hemophagocytic syndromes, macrophage activation syndrome, sepsis and acute kidney injury, although in some diseases, IL 18 is protective. IL 18 plays a major role in the production of interferon-g from natural killer cells. The IL 18BP has been used safely in humans and clinical trials of IL 18BP as well as neutralizing anti-IL 18 antibodies are in clinical trials. This review updates the biology of IL 18 as well as its role in human disease

IL-32, a recently discovered proinflammatory cytokine with four isoforms, induces IL-1β, TNF-α, IL-6, and chemokines. Here, we used ligand (IL-32α) affinity chromatography in an attempt to isolate an IL-32α soluble receptor or binding protein. Recombinant IL-32α was covalently immobilized on agarose, and preparations of concentrated crude human urinary proteins were applied for chromatographic separation. A specific 30-kDa protein eluted from the column during acid washing and was identified by mass spectrometry as proteinase 3 (PR3) and confirmed by N-terminal microsequencing. PR3, a neutrophil granule serine protease, exists in a soluble or membrane form and is the major autoantigen for autoantibodies in the systemic vasculitic disease, Wegener's granulomatosis. The affinity of IL-32α to PR3 was determined by surface plasmon resonance. The dissociation constants were 2.65 ± 0.4 nM for urinary PR3 and 1.2 ± 0.05 nM for neutrophil-derived PR3. However, irreversible inactivation of PR3 enzymatic activity did not significantly change binding to the cytokine. Nevertheless, limited cleavage of IL-32 yielded products consistent with PR3 enzyme activity. Moreover, after limited cleavage by PR3, IL-32α was more active than intact IL-32α in inducing macrophage inflammatory protein-2 in mouse macrophages and IL-8 in human peripheral blood mononuclear cells. We suggest that PR3 is a specific IL-32α binding protein, independent of its enzymatic activity. However, limited cleavage of IL-32α by PR3 enhances activities of the cytokine. Therefore, specific inhibition of PR3 activity to process IL-32 or neutralization of IL-32 by inactive PR3 or its fragments may reduce the consequences of IL-32 in immune regulated diseases.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition due to the association of an infectious agent with lymphocyte cytotoxicity defects, either of congenital genetic origin in children or presumably acquired in adults. In HLH patients, an excess of lymphocyte or macrophage cytokines, such as IFN-γ and TNFα is present in serum. In animal models of the disease, IFN-γ and TNF-α have been shown to play a central pathogenic role. In humans, unusually high concentrations of IL-18, an inducer of IFN-γ, and TNF-α have been reported, and are associated with an imbalance between IL-18 and its natural inhibitor IL-18 binding protein (IL-18BP) resulting in an excess of free IL-18. Here we studied whether IL-18BP could reduce disease severity in an animal model of HLH. Mouse cytomegalovirus infection in perforin-1 knock-out mice induced a lethal condition similar to human HLH characterized by cytopenia with marked inflammatory lesions in the liver and spleen as well as the presence of hemophagocytosis in bone marrow. IL-18BP treatment decreased hemophagocytosis and reversed liver as well as spleen damage. IL-18BP treatment also reduced both IFN-γ and TNF-α production by CD8⁺ T and NK cells, as well as Fas ligand expression on NK cell surface. These data suggest that IL-18BP is beneficial in an animal model of HLH and in combination with anti-infectious therapy may be a promising strategy to treat HLH patients.

Interleukin-18 (IL-18) serves a dual function in the immune system, acting as a “double-edged sword” cytokine. Depending on the microenvironment and timing, IL-18 can either drive harmful inflammation or restore immune homeostasis. Pathologies characterized by elevated IL-18, recently proposed to be termed IL-18opathies, highlight the therapeutic potential for IL-18 blockade. IL-18 Binding Protein (IL-18BP) is one of only four natural cytokine antagonists encoded by a separate gene, distinguishing it from canonical soluble receptors. IL-18BP’s exceptionally high affinity and slow dissociation rate make it an effective regulator of IL-18, essential for maintaining immune balance and influencing disease outcomes, and positions IL-18BP as a promising alternative to more aggressive treatments that carry risks of severe infections and other complications. Tadekinig alfa, the drug form of IL-18BP, represents a targeted therapy that modulates the IL-18/IL-18BP axis, offering a safe adverse-effect-free option. With orphan drug designation, Phase III clinical trial completion, and seven years of compassionate use, Tadekinig alfa holds promise in treating autoimmune and inflammatory diseases, cancer, and genetically linked disorders. Levels of IL-18, free IL-18 and IL-18BP, may serve as biomarkers for disease severity and therapeutic response. Given its pivotal role in immune balance, the IL-18/IL-18BP dyad has attracted interest from over ten pharmaceutical companies and startups, which are currently developing innovative strategies to either inhibit or enhance IL-18 activity depending on the therapeutic need. The review focuses on the features of the dyad members and screens the therapeutic approaches.