Recombinant human IL-18 protein - Bioactive cytokine

IL-18 background

Interleukin-18 (IL-18) is a member of the IL-1/Toll-like receptor cytokine superfamily, a group of cytokines that play important roles in host defense, immune regulation, and inflammation [1-3]. It is principally produced by macrophages, dendritic cells, endothelial cells, and epithelial cells. Like IL-1β, it is synthesized as an inactive precursor that is cleaved and processed into its mature bioactive form by caspase-1 upon inflammasome activation [1, 2].

IL-18 mediates its biological effects through the IL-1R5 receptor (also known as IL-18Rα, CD218a) and the IL-1R7 accessory protein (also known as IL-18RAcP, IL-18β, CD218b) [1, 2, 4]. Upon ligand binding, IL-1Rs dimerize through their Toll/interleukin-1 resistance (TIR) domains to recruit the MyD88 adaptor protein, which then couples to IL-1R-associated kinases (IRAKs) and tumor necrosis factor receptor-associated factor 6 (TRAF6). This leads to the activation of key transcription factors, including NF-κB, AP-1, and IRFs [1-4].

Formerly known as interferon-γ (IFN-γ) inducing factor, IL-18 drives pro-inflammatory responses from both the innate and adaptive immune systems [1-3]. It is primarily described as a potent inducer of NK (natural killer) cell activation and the polarization of CD4+ T-helper cells into Th1 or Th2 types, depending on the surrounding cytokine milieu. In addition, IL-18 exhibits characteristics of other proinflammatory cytokines, including increases in cell adhesion molecules, nitric oxide synthesis, and chemokine production. IL-18 plays a prominent role in fighting microbial infections caused by viruses, intracellular bacteria, or fungi. 

The activity of mature IL-18 is controlled by the IL-18BP (IL-18 binding protein), which functions as a decoy receptor, preventing IL-18 from engaging with the signaling receptor [1-3].
 

Relevance for therapeutics development

Excessive IL-18 signaling, either due to gain-of-function mutations or inefficient negative regulation, is linked to inflammatory disorders (e.g., macrophage activation syndrome (MAS), systemic juvenile idiopathic arthritis (sJIA), adult-onset Still’s disease (AOSD), metabolic syndrome) and autoimmune diseases (e.g., Crohn’s disease, systemic lupus erythematosus (SLE)) [1, 2].

Therapeutic strategies include recombinant human IL-18BP (Tadekinig alpha) and an anti-human IL-18 monoclonal antibody (Camoteskimab) to neutralize IL-18 signaling. Conversely, DR-18 (ST-067), an IL-18 mutein resistant to IL-18BP decoy receptor, has shown promising results in augmenting immune responses to cancer [1].
 

​References:

1. Landy, E., et al., 2024. Biological and clinical roles of IL-18 in inflammatory diseases. Nat Rev Immunol. 20(1):33-47.
2. Kaplancki, G., et al., 2017. Interleukin-18: Biological properties and role in disease pathogenesis. Immunol Rev. 281(1):138-153.
3. Mantovani, A., et al., 2019. Interleukin-1 and Related Cytokines in the Regulation of Inflammation and Immunity. Immunity. 50(4): p. 778-795.
4. Gaballa, J.M., et al., 2024. International nomenclature guidelines for the IL-1 family of cytokines and receptors. Nature Immunology. 25(4): p. 581-582.