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Biological and clinical roles of IL-18 in inflammatory diseases

Nature Reviews Rheumatology volume 20, pages 33–47 (2024)Cite this article

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Abstract

Several new discoveries have revived interest in the pathogenic potential and possible clinical roles of IL-18. IL-18 is an IL-1 family cytokine with potent ability to induce IFNγ production. However, basic investigations and now clinical observations suggest a more complex picture. Unique aspects of IL-18 biology at the levels of transcription, activation, secretion, neutralization, receptor distribution and signalling help to explain its pleiotropic roles in mucosal and systemic inflammation. Blood biomarker studies reveal a cytokine for which profound elevation, associated with detectable ‘free IL-18’, defines a group of autoinflammatory diseases in which IL-18 dysregulation can be a primary driving feature, the so-called ‘IL-18opathies’. This impressive specificity might accelerate diagnoses and identify patients amenable to therapeutic IL-18 blockade. Pathogenically, human and animal studies identify a preferential activation of CD8+ T cells over other IL-18-responsive lymphocytes. IL-18 agonist treatments that leverage the site of production or subversion of endogenous IL-18 inhibition show promise in augmenting immune responses to cancer. Thus, the unique aspects of IL-18 biology are finally beginning to have clinical impact in precision diagnostics, disease monitoring and targeted treatment of inflammatory and malignant diseases.

Key points

  • Unique features of IL-18 create challenges in investigating its biology, but also offer opportunities for therapeutic modulation.

  • Most cytokines are non-specific biomarkers, but profoundly elevated IL-18 levels (consistent with detectable free IL-18) are specific for macrophage activation syndrome-prone and PSTPIP1-related diseases.

  • IL-18 binding protein is a valuable biomarker of IFNγ activity.

  • IL-18-mediated pathology includes multiple organs and systems, particularly systemic hyperinflammation, which is consistent with the pleiotropic amplification of multiple pathways, particularly IFNγ.

  • Ongoing efforts to both block and augment IL-18 function will better elucidate its role in health, cancer and rheumatic diseases.

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Fig. 1: Origins, extracellular fate and signalling of IL-18.
Fig. 2: Pathological manifestations of the IL-18opathies relative to sources of IL-18 production.
Fig. 3: Genotype/phenotype and domain architecture of genes implicated in monogenic IL-18opathies.

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Authors and Affiliations

  1. Program in Microbiology and Immunology, University of Pittsburgh, Pittsburgh, PA, USA

    Emily Landy & Scott Canna

  2. Division of Rheumatology and Immune Dysregulation Program, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Hallie Carol & Scott Canna

  3. Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

    Hallie Carol & Scott Canna

  4. Translational Science and Therapeutics, Fred Hutchinson Cancer Center, Seattle, WA, USA

    Aaron Ring

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  1. Emily Landy
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  2. Hallie Carol
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  3. Aaron Ring
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  4. Scott Canna
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E.L., H.C. and S.C. researched data for the article. All authors contributed substantially to discussion of the content, wrote the article and reviewed and/or edited the manuscript before submission.

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Correspondence to Scott Canna.

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Competing interests

S.C. is a site PI for a clinical trial run by Novartis and also does consulting for Simcha Therapeutics, Apollo Therapeutics, and Sobi. The other authors declare no competing interests.

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Nature Reviews Rheumatology thanks Cem Gabay, Charles Dinarello and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Landy, E., Carol, H., Ring, A. et al. Biological and clinical roles of IL-18 in inflammatory diseases. Nat Rev Rheumatol 20, 33–47 (2024). https://doi.org/10.1038/s41584-023-01053-w

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