Interleukin-18, more than a Th1 cytokine
Abstract
Together with IL-12 or IL-15, interleukin-18 (IL-18) plays a major role in the production of interferon-γ from T-cells and natural killer cells; thus, IL-18 is considered to have a major role in the Th1 response. However, without IL-12, IL-18 is proinflammatory in an IFNγ independent manner. IL-18 is a member of the IL-1 family of cytokines and similar to IL-1β, the cytokine is synthesized as an inactive precursor requiring processing by caspase-1 into an active cytokine. IL-18 is also present as an integral membrane protein but requires caspase-1 for full activity in order to induce IFNγ. Uniquely, unlike IL-1β, the IL-18 precursor is constitutively present in nearly all cells in healthy humans and animals. The activity of IL-18 is balanced by the presence of a high-affinity, naturally occurring IL-18 binding protein (IL-18BP). In humans, increased disease severity can be associated with an imbalance of IL-18 to IL-18BP such that the levels of free IL-18 are elevated in the circulation. Increasing number of studies have expanded the role of IL-18 in mediating inflammation in animal models of disease using the IL-18BP, IL-18 deficient mice, neutralization of IL-18 or deficiency in the IL-18 receptor alpha chain. A role for IL-18 has been implicated in several autoimmune diseases, myocardial function, emphysema, metabolic syndromes, psoriasis, inflammatory bowel disease, macrophage activation syndrome, sepsis and acute kidney injury, although paradoxically, in some models of disease, IL-18 is protective. The IL-18BP has been used safely in humans and clinical trials of IL-18BP as well as neutralizing anti-IL-18 antibodies are being tested in various diseases.
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The ratio of free interleukin-18 to bound interleukin-18-IL18BP complexes in serum is an important indicator of the severity of macrophage activation syndrome.
“The ratio of free interleukin-18 to bound interleukin-18–IL18BP complexes in serum is an important indicator of the severity of the macrophage activation syndrome.44,47”
From Cytokine storm (2020) · cites this paper as [47]
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Mechanisms of Inhibition of Collagen-Induced Arthritis by Murine IL-18 Binding Protein
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Self-citationIL-18 cDNA vaccination protects mice from spontaneous lupus-like autoimmune disease
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Self-citationAn IFN-γ-Independent Proinflammatory Role of IL-18 in Murine Streptococcal Cell Wall Arthritis
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Self-citationProinterleukin-18 Is Activated by Meprin β in Vitro and in Vivo in Intestinal Inflammation
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Interleukin-18 in Intestinal Inflammation: Friend and Foe?
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Daily administration of interleukin-18 causes myocardial dysfunction in healthy mice
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Interferon-γ Mediates Gene Expression of IL-18 Binding Protein in Nonleukocytic Cells
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Adenoviral delivery of IL-18 binding protein C ameliorates Collagen-Induced Arthritis in mice
Smeets, R. L., van de Loo, F. A. J., Arntz, O. J., Bennink, M. B., Joosten, L. A. B., & van den Berg, W. B. (2003) · Gene Therapy · doi:10.1038/sj.gt.3301986 · Cited by 91 · see citing works
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Interleukin-1β converting enzyme (caspase-1) in intestinal inflammation
Siegmund, B. (2002) · Biochemical Pharmacology · doi:10.1016/s0006-2952(02)01064-x · Cited by 89 · see citing works
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IL‐18 Activity in Systemic Lupus Erythematosus
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Self-citationTakeuchi, D., Yoshidome, H., Kato, A., Ito, H., Kimura, F., Shimizu, H., Ohtsuka, M., Morita, Y., & Miyazaki, M. (2004) · Hepatology · doi:10.1002/hep.20117 · Cited by 84 · see citing works
Neutralization of IL-18 attenuates lipopolysaccharide-induced myocardial dysfunction
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Reznikov, L. L., Kim, S. H., Westcott, J. Y., Frishman, J. I., Fantuzzi, G., Novick, D., Rubinstein, M., & Dinarello, C. A. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.040582597 · Cited by 79 · see citing works
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Self-citationInterleukin-18 binding protein transgenic mice are protected against ischemic acute kidney injury
He, Z., Lu, L., Altmann, C. J., Hoke, T. S., Ljubanović, D. G., Jani, A. H., Dinarello, C. A., Faubel, S. G., & Edelstein, C. L. (2008) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.90288.2008 · Cited by 76 · see citing works
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Accessory Protein-Like Is Essential for IL-18-Mediated Signaling
Cheung, H., Chen, N., Cao, Z., Ono, N., Ohashi, P. S., & Yeh, W. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.174.9.5351 · Cited by 73 · see citing works
Correspondence of the Functional Epitopes of Poxvirus and Human Interleukin-18-Binding Proteins
Xiang, Y., & Moss, B. A. (2001) · Journal of Virology · doi:10.1128/jvi.75.20.9947-9954.2001 · Cited by 73 · see citing works
Higher-dose Anakinra Is Effective in a Case of Medically Refractory Macrophage Activation Syndrome
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Effect of interleukin-18 on mouse core body temperature
Gatti, S., Beck, J., Fantuzzi, G., Bartfai, T., & Dinarello, C. A. (2002) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00393.2001 · Cited by 72 · see citing works
Self-citationElevated systemic levels of free interleukin-18 (IL-18) in patients with Crohn's disease.
Ludwiczek, O., Kaser, A., Novick, D., Dinarello, C. A., Rubinstein, M., & Tilg, H. (2005) · PubMed · Cited by 69 · see citing works
Self-citationBlockade of IL-18 Receptor Signaling Delays the Onset of Autoimmune Disease in MRL- Fas lpr Mice
Kinoshita, K., Yamagata, T., Nozaki, Y., Sugiyama, M., Ikoma, S., Funauchi, M., & Kanamaru, A. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.173.8.5312 · Cited by 66 · see citing works
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The effect of daily administration of IL-18 on cardiac structure and function
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Interferon-αinduces interleukin-18 binding protein in chronic hepatitis C patients
Kaser, A., Novick, D., Rubinstein, M., Siegmund, B., Enrich, B., Koch, R., Vogel, W., Kim, S. H., Dinarello, C. A., & Tilg, H. (2002) · Clinical & Experimental Immunology · doi:10.1046/j.1365-2249.2002.01911.x · Cited by 56 · see citing works
Self-citationCytokine profiles in children with primary Epstein–Barr virus infection
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Self-citationGeneration and characterization of mice transgenic for human IL-18-binding protein isoforma
Fantuzzi, G., Banda, N. K., Guthridge, C. J., Vondracek, A., Kim, S., Siegmund, B., Azam, T., Sennello, J. A., Dinarello, C. A., & Arend, W. P. (2003) · Journal of Leukocyte Biology · doi:10.1189/jlb.0503230 · Cited by 54 · see citing works
Self-citationIL-27 Regulates IL-18 Binding Protein in Skin Resident Cells
Wittmann, M., Doble, R., Bachmann, M., Pfeilschifter, J. M., Werfel, T., & Mühl, H. (2012) · PLoS ONE · doi:10.1371/journal.pone.0038751 · Cited by 52 · see citing works
Interleukin-18 as a mediator of systemic juvenile idiopathic arthritis
Jelušić, M., Lukić, I. K., Tambić-Bukovac, L., Dubravčić, K., Malčić, I., Rudan, I., & Batinić, D. (2006) · Clinical Rheumatology · doi:10.1007/s10067-006-0474-0 · Cited by 49 · see citing works
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Self-citationInterleukin-18 Binding Protein in the Sera of Patients with Wegener’s Granulomatosis
Novick, D., Elbirt, D., Dinarello, C. A., Rubinstein, M., & Sthoeger, Z. M. (2008) · Journal of Clinical Immunology · doi:10.1007/s10875-008-9217-0 · Cited by 41 · see citing works
Self-citationMultimodality Imaging of IL-18–Binding Protein-Fc Therapy of Experimental Lung Metastasis
Cao, Q., Cai, W., Niu, G., He, L., & Chen, X. S. (2008) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-08-0049 · Cited by 40 · see citing works
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Self-citationMommsen, P., Frink, M., Pape, H., van Griensven, M., Probst, C. P., Gaulke, R., Krettek, C., & Hildebrand, F. (2008) · Injury · doi:10.1016/j.injury.2008.08.007 · Cited by 39 · see citing works
Murray, D. R. P., Mummidi, S., Valente, A. J., Yoshida, T., Somanna, N. K., Delafontaine, P., Dinarello, C. A., & Chandrasekar, B. (2011) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2011.09.022 · Cited by 38 · see citing works
Self-citationThe heart on fire: inflammasome and cardiomyopathy
Abbate, A. (2013) · Experimental Physiology · doi:10.1113/expphysiol.2012.069021 · Cited by 37 · see citing works
Elevated levels of circulating IL-18BP and perturbed regulation of IL-18 in schizophrenia
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Activation of caspase-1 dependent interleukins in developmental brain trauma
Sifringer, M., Stefovska, V. G., Endesfelder, S., Stahel, P. F., Genz, K., Dzietko, M., Ikonomidou, C., & Felderhoff‐Mueser, U. (2006) · Neurobiology of Disease · doi:10.1016/j.nbd.2006.11.003 · Cited by 26 · see citing works
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Immunotherapeutic Applications of IL-18
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Suppressive Effects of Interleukin-18 on Liver Function in Rat Liver Allografts
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Is interleukin‐18 useful for monitoring rheumatoid arthritis?
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Involvement of Interleukin-18 in Acute Graft-Versus-Host Disease in Mice
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Cloning and characterization of rhesus IL-18 binding protein, a natural antagonist to IL-18
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Fajgenbaum, D. C., & June, C. H. (2020) · New England Journal of Medicine · doi:10.1056/nejmra2026131 · Cited by 3,196 · see citing works
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Biomarkers in acute kidney injury – pathophysiological basis and clinical performance
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Molecular mechanisms and functions of pyroptosis in inflammation and antitumor immunity
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The IL-1 cytokine family and its role in inflammation and fibrosis in the lung
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Biomarkers of acute kidney injury: the pathway from discovery to clinical adoption
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Self-citationOf Inflammasomes and Alarmins: IL-1β and IL-1α in Kidney Disease
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- Authors
- Novick, D., Kim, S., Kaplanski, G., & Dinarello, C. A.
- Affiliations
- Weizmann Institute of Science (IL)
- Konkuk University (KR)
- Aix-Marseille Université (FR)
- University of Colorado Denver (US)
- Corresponding author
- Dinarello, Charles A.
- Venue
- Seminars in Immunology
- Publisher
- Elsevier BV
- Published
- 2013-12
- Volume
- 25
- Issue
- 6
- Pages
- 439-448
- ISSN
- 1044-5323 (ISSN-L)
- OpenAlex
- W2005242977
- Cited by
- 280
- References
- 165
- Citations by year
- 2026: 7 · 2025: 13 · 2024: 16 · 2023: 23 · 2022: 20 · 2021: 23 · 2020: 36 · 2019: 21 · 2018: 29 · 2017: 28 · 2016: 35 · 2015: 20 · 2014: 9
- FWCI
- 2.19
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Seminars in Immunology (publishedVersion)
- PubMed (publishedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Funders
- National Cancer Institute (CA 046934, P30CA046934)
- National Institute of Allergy and Infectious Diseases (AI‑15614)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR‑45584, R01AR045584)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- IL-18, IL-18BP, Th1 response, interferon-gamma, IL-18 receptor alpha, IL-1 family cytokines, pro-inflammatory effects, autoimmune disease, macrophage activation syndrome, sepsis, acute kidney injury
- MeSH terms
- Animals, Autoimmune Diseases, Heart Diseases, Humans, Inflammation, Interferon-gamma, Killer Cells, Natural, Shock, Septic, Th1 Cells, Interleukin-12, Inflammation Mediators, Caspase 1, Interleukin-18, Intercellular Signaling Peptides and Proteins, Mice, Macrophage Activation Syndrome
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