Interleukin-18 and IL-18 Binding Protein
Open accessAbstract
Interleukin-18 (IL-18) is a member of the IL-1 family of cytokines. Similar to IL-1β, IL-18 is synthesized as an inactive precursor requiring processing by caspase-1 into an active cytokine but 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, hemophagocytic syndromes, macrophage activation syndrome, sepsis, and acute kidney injury, although in some models of disease, IL-18 is protective. IL-18 plays a major role in the production of interferon-γ from T-cells and natural killer cells. The IL-18BP has been used safely in humans and clinical trials of IL-18BP as well as neutralizing anti-IL-18 antibodies are in clinical trials. This review updates the biology of IL-18 as well as its role in human disease.
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IL18BP normally prevents interleukin-18 from binding to its receptor, keeping the proinflammatory effects of interleukin-18 in check.
“The proinflammatory effects of interleukin-18 are normally kept in check by the interleukin-18–binding protein (IL18BP), which prevents the binding of interleukin-18 to its receptor.46”
From Cytokine storm (2020) · cites this paper as [46]
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Siegmund, B. (2010) · Immunity · doi:10.1016/j.immuni.2010.03.010 · Cited by 102 · see citing works
Carrascal, M. T., Mendoza, L., Valcárcel, M., Salado, C., Egilegor, E., Tellería, N., Vidal‐Vanaclocha, F., & Dinarello, C. A. (2003) · PubMed · Cited by 102 · see citing works
Self-citationSümegi, J., Barnes, M., Nestheide, S. V., Molleran-Lee, S., Villanueva, J. M., Zhang, K., Risma, K., Grom, A. A., & Filipovich, A. H. (2011) · Blood · doi:10.1182/blood-2010-08-300046 · Cited by 98 · see citing works
Daily administration of interleukin-18 causes myocardial dysfunction in healthy mice
Woldbæk, P. R., Sande, J. B., Strømme, T. A., Lunde, P., Djurovic, S., Lyberg, T., Christensen, G., & Tønnessen, T. (2005) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.01179.2004 · Cited by 97 · see citing works
Interferon-γ Mediates Gene Expression of IL-18 Binding Protein in Nonleukocytic Cells
Mühl, H., Kämpfer, H., Bosmann, M., Frank, S., Radeke, H. H., & Pfeilschifter, J. M. (2000) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1999.2064 · Cited by 97 · see citing works
Sirota, J. C., Walcher, A. M., Faubel, S. G., Jani, A. H., McFann, K., Devarajan, P., Davis, C. L., & Edelstein, C. L. (2013) · BMC Nephrology · doi:10.1186/1471-2369-14-17 · Cited by 96 · see citing works
Novick, D., Elbirt, D., Miller, G., Dinarello, C. A., Rubinstein, M., & Sthoeger, Z. M. (2009) · Journal of Autoimmunity · doi:10.1016/j.jaut.2009.08.002 · Cited by 95 · see citing works
Self-citationBellora, F., Castriconi, R., Doni, A., Cantoni, C., Moretta, L., Mantovani, A., Moretta, A., & Bottino, C. (2012) · European Journal of Immunology · doi:10.1002/eji.201142173 · Cited by 92 · see citing works
Maeno, N., Takei, S., Imanaka, H., Yamamoto, K., Kuriwaki, K., Kawano, Y., & Oda, H. (2004) · Arthritis & Rheumatism · doi:10.1002/art.20268 · Cited by 91 · see citing works
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
Ludwiczek, O., Kaser, A., Novick, D., Dinarello, C. A., Rubinstein, M., Vogel, W., & Tilg, H. (2002) · Journal of Clinical Immunology · doi:10.1023/a:1020600230977 · Cited by 87 · see citing works
Self-citationTak, P. P., Bacchi, M., & Bertolino, M. (2006) · European Journal of Drug Metabolism and Pharmacokinetics · doi:10.1007/bf03191127 · Cited by 87 · see citing works
IL‐18 Activity in Systemic Lupus Erythematosus
Favilli, F., Anzilotti, C., Martinelli, L., Quattroni, P., Martino, S. D., Pratesi, F., Neumann, D., Beermann, S., Novick, D., Dinarello, C. A., et al. (2009) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2009.04742.x · Cited by 87 · see citing works
Self-citationNeutralization of IL-18 attenuates lipopolysaccharide-induced myocardial dysfunction
Raeburn, C. D., Dinarello, C. A., Zimmerman, M. A., Calkins, C. M., Pomerantz, B. J., McIntyre, R. C., Harken, A. H., & Meng, X. (2002) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00043.2002 · Cited by 83 · see citing works
Self-citationReimers, A., Fux, C., & Spaeth, P. (2002) · Swiss Medical Weekly · doi:10.4414/smw.2002.09941 · Cited by 82 · see citing works
Emmanuilidis, K., Weighardt, H., Matevossian, E., Heidecke, C.-D., Ulm, K., Bartels, H., Siewert, J. R., & Holzmann, B. (2002) · Shock · doi:10.1097/00024382-200210000-00002 · Cited by 80 · see citing works
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
Self-citationSennello, J. A., Fayad, R., Pini, M., Gove, M. E., Ponemone, V., Cabay, R. J., Siegmund, B., Dinarello, C. A., & Fantuzzi, G. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0804091105 · Cited by 79 · see citing works
Self-citationInvestigation of nicotine binding to THP-1 cells : evidence for a non-cholinergic binding site
Morgan, D., Parsons, M., & Whelan, C. J. (2001) · University of Hertfordshire Research Archive (University of Hertfordshire) · doi:10.1016/s0006-2952 · Cited by 77 · see citing works
Bauer, C. A., Loher, F., Dauer, M., Mayer, C., Lehr, H. A., Schönharting, M., Hallwachs, R., Endres, S., & Eigler, A. (2007) · Digestive Diseases and Sciences · doi:10.1007/s10620-007-9802-8 · Cited by 75 · 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
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-citationLi, S., Goorha, S., Ballou, L. R., & Blatteis, C. M. (2003) · Brain Research · doi:10.1016/j.brainres.2003.08.033 · Cited by 64 · see citing works
The effect of daily administration of IL-18 on cardiac structure and function
Platis, A. G., Yu, Q., Moore, D., Khojeini, E., Tsau, P. H., & Larson, D. (2008) · Perfusion · doi:10.1177/0267659108101511 · Cited by 58 · see citing works
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
Wada, T., Muraoka, M., Yokoyama, T., Toma, T., Kanegane, H., & Yachie, A. (2013) · Pediatric Blood & Cancer · doi:10.1002/pbc.24480 · Cited by 56 · see citing works
Expression of ADAM33 Is a Novel Regulatory Mechanism in IL-18-Secreted Process in Gastric Cancer
Kim, K.-E., Song, H., Hahm, C., et al. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0801695 · Cited by 52 · see citing works
IL-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
Interleukin-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-citationThompson, S. R., Novick, D., Stock, C. J. W., Sanders, J., Brull, D. J., Cooper, J. A., Woo, P. M., Miller, G. J., Rubinstein, M., & Humphries, S. E. (2007) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.107.149245 · Cited by 39 · see citing works
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
Immunotherapeutic Applications of IL-15
Croce, M., Orengo, A. M., Azzarone, B. G., et al. (2012) · Immunotherapy · doi:10.2217/imt.12.92 · Cited by 38 · see citing works
Elevated levels of circulating IL-18BP and perturbed regulation of IL-18 in schizophrenia
Palladino, I., Salani, F., Ciaramella, A., Rubino, I. A., Caltagirone, C., Fagioli, S., Spalletta, G., & Bossù, P. (2012) · Journal of Neuroinflammation · doi:10.1186/1742-2094-9-206 · Cited by 35 · see citing works
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Immunotherapeutic Applications of IL-18
Tsutsui, H., & Nakanishi, K. (2012) · Immunotherapy · doi:10.2217/imt.12.137 · Cited by 25 · see citing works
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Is interleukin‐18 useful for monitoring rheumatoid arthritis?
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- Authors
- Dinarello, C. A., Novick, D., Kim, S., & Kaplanski, G.
- Affiliations
- University of Colorado Denver (US)
- Weizmann Institute of Science (IL)
- Konkuk University (KR)
- Aix-Marseille Université (FR)
- Corresponding author
- Dinarello, Charles A.
- Venue
- Frontiers in Immunology
- Publisher
- Frontiers Media SA
- Published
- 2013
- Volume
- 4
- Pages
- 289-289
- ISSN
- 1664-3224 (ISSN-L)
- PMC
- PMC3792554
- OpenAlex
- W2064856766
- Cited by
- 938
- References
- 126
- Citations by year
- 2026: 50 · 2025: 46 · 2024: 84 · 2023: 107 · 2022: 112 · 2021: 109 · 2020: 80 · 2019: 75 · 2018: 66 · 2017: 66 · 2016: 56 · 2015: 49 · 2014: 35 · 2013: 2
- FWCI
- 5.00
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Frontiers in Immunology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Radboud Repository (Radboud University) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion, other-oa)
- Funders
- Agence Nationale de la Recherche
- National Institutes of Health (CA-04-6934, 15614, AI‐15614)
- National Institute of Allergy and Infectious Diseases (R56AI015614, R01AI015614)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (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-18 binding protein, IL-1 family cytokines, inflammation, autoimmune disease, interferon-gamma, natural killer cells, sepsis, acute kidney injury, macrophage activation syndrome, hemophagocytic lymphohistiocytosis, inflammatory bowel disease, psoriasis, emphysema, metabolic syndrome
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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