Open Access

REVIEW

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

Simone Negrini^1,2,*, Stefania Nicola^1,2, Iuliana Badiu^1,2, Anna Quinternetto^1,2, Ilaria Vitali^1,2, Luca Lo Sardo^1,2, Luisa Brussino^1,2

1 Department of Medical Sciences, University of Turin, Corso Dogliotti, Turin, Italy
2 Immunology and Allergy Unit, AO Ordine Mauriziano di Torino, Via Magellano, Turin, Italy

* Corresponding Author: Simone Negrini. Email:

European Cytokine Network 2026, 37(3), 151-168. https://doi.org/10.32604/ecn.2026.083788

Received 10 April 2026; Accepted 13 July 2026; Issue published 28 September 2026

Abstract

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.

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Keywords

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