Interleukin-18 signaling pathway (IL-18 pathway)

The Interleukin-18 (IL-18) signaling pathway is a key proinflammatory axis within the IL-1 cytokine family, primarily responsible for regulating innate and adaptive immune responses [1, 11]. Signaling is initiated when mature IL-18, processed from its inactive precursor by caspase-1, binds to the IL-18 receptor alpha (IL-18Rα) and recruits the accessory protein IL-18Rβ to form a high-affinity ternary complex [1, 12]. This complex activates downstream pathways such as NF-κB, MAPK, and PI3K/AKT, leading to the production of interferon-gamma (IFN-γ) and other inflammatory mediators [3, 12]. Pathologically, an imbalance between IL-18 and its natural antagonist, IL-18 binding protein (IL-18BP), drives chronic inflammation in diseases like adult-onset Still's disease, systemic juvenile idiopathic arthritis, and various autoimmune conditions [13, 17]. In oncology, the pathway exhibits a dual role, potentially enhancing anti-tumor immunity or promoting tumor progression and chemoresistance in certain cancers like glioma [6, 9]. Therapeutic interventions include recombinant IL-18BP (tadekinig alfa) and monoclonal antibodies (GSK1070806) to inhibit signaling in inflammatory disorders, as well as decoy-resistant IL-18 variants to stimulate immune responses in cancer [5, 8].

Other names

IL-18/IL-18R axisInterferon-gamma inducing factor pathwayIL-18 signalingIL-18/IL-18R signaling pathway

Inhibition of IL-18 signaling through ligand neutralization, receptor blockade, or recombinant binding protein supplementation; and activation of the pathway using decoy-resistant IL-18 variants in oncology.