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Semin Immunol. 2013 Dec 15;25(6):439-48. doi: 10.1016/j.smim.2013.10.014. Epub 2013 Nov 22.

Interleukin-18, more than a Th1 cytokine.

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Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
Department of Biomedical Science and Technology, Konkuk University, Seoul, Republic of Korea.
UMR-S1076, Aix Marseille Université, Campus Timone, Marseille, France; Service de Médecine Interne, Hôpital de la Conception, Assistance Publique Hôpitaux de Marseille, Marseille, France.
Department of Medicine, University of Colorado Denver, Aurora, CO, United States; Department of Medicine, University Medical Center Nijmegen, Nijmegen, The Netherlands. Electronic address:


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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