TY  - EJOU
AU  - Negrini, Simone 
AU  - Nicola, Stefania 
AU  - Badiu, Iuliana 
AU  - Quinternetto, Anna 
AU  - Vitali, Ilaria 
AU  - Sardo, Luca Lo 
AU  - Brussino, Luisa 

TI  - The interleukin-18/Interleukin-18 binding protein axis across allergy, systemic autoimmunity, and hyperinflammation: from total to free IL-18
T2  - European Cytokine Network

PY  - 2026
VL  - 37
IS  - 3
SN  - 1952-4005

AB  - Interleukin-18 (IL-18) is a pleiotropic IL-1-family cytokine whose clinical relevance depends strongly on context. A central reason is that IL-18 activity is constrained by interleukin-18 binding protein (IL-18BP), a high-affinity endogenous antagonist that limits the free, bioactive cytokine fraction. This review re-examines the IL-18/IL-18BP axis across a clinical gradient from barrier dysfunction and allergic disease, through systemic autoimmunity, to Still disease, macrophage activation syndrome, hemophagocytic lymphohistiocytosis, and monogenic IL-18opathies. We emphasize that total IL-18 elevation does not necessarily imply pathogenic IL-18 activity; the key translational question is whether IL-18BP-mediated restraint remains sufficient. In barrier disorders and systemic autoimmunity, IL-18 often behaves as a contextual amplifier or biomarker-amplifier axis. In hyperinflammatory and selected monogenic disorders, extreme IL-18 production may exceed endogenous antagonism, allowing free IL-18 to emerge and acquire diagnostic, mechanistic, and therapeutic relevance. Interpreting total IL-18, IL-18BP/free IL-18, and downstream IFN-γ/CXCL9 signals together may improve biomarker interpretation and guide rational targeting of the pathway.
KW  - Interleukin-18; IL-18 binding protein; free IL-18; macrophage activation syndrome; hemophagocytic lymphohistiocytosis; systemic lupus erythematosus; still’s disease; hyperinflammation

DO  - 10.32604/ecn.2026.083788