IL-18

Interleukin-18 (IL-18) is a proinflammatory cytokine of the IL-1 family that induces IFN-γ production and activates both innate and adaptive immune cells^[1][2]. Mechanistically, IL-18 is synthesized as an inactive precursor and requires cleavage by caspase-1 to become biologically active, engaging the IL-18 receptor complex composed of IL-18Rα and IL-18Rβ subunits^[3][4]. IL-18 signaling activates downstream pathways including MyD88, IRAK, TRAF-6, and NF-κB, leading to the transcription of proinflammatory genes and chemokines^[5][6]. Compared with related IL-1 family members, IL-18 exhibits distinct kinetics and cell-type specificity, sustaining Th1 responses without necessarily inducing persistent high IFN-γ levels^[7][8]. In disease models, IL-18 contributes to rheumatoid arthritis by promoting GM-CSF, TNF-α, and matrix metalloproteinase production in synovial tissue and accelerates atherosclerosis through IFN-γ-mediated macrophage activation^[9][10][11]. IL-18 is implicated in autoinflammatory syndromes, cardiovascular hypertrophy, liver injury, and dermatological inflammation, where dysregulation of IL-18 drives pathology^[12][13][14]. Endogenous IL-18-binding protein (IL-18BP) serves as a high-affinity antagonist that neutralizes IL-18, preventing excessive inflammation and providing a therapeutic avenue for intervention^[15][12][5]. Agonist or recombinant IL-18 therapies can enhance cytotoxic lymphocyte function in cancer models, whereas IL-18BP or Tadekinig alfa administration effectively mitigates systemic inflammatory responses^[8][7][4].