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Review
. 2013 Oct 8:4:289.
doi: 10.3389/fimmu.2013.00289.

Interleukin-18 and IL-18 binding protein

Charles A Dinarello  1 , Daniela Novick, Soohyun Kim, Gilles Kaplanski
Affiliations
Review

Interleukin-18 and IL-18 binding protein

Charles A Dinarello et al. Front Immunol. .

Abstract

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.

Keywords: autoimmune diseases; inflammasomes; inflammation; interleukin-1; macrophages.

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Figures

Figure 1
Figure 1
Interleukin-18 signal transduction. IL-18 forms a signaling complex by binding to the IL-18 alpha chain (IL-18Rα). The co-receptor, termed IL-18 receptor beta chain (IL-18Rβ), is recruited to form a high affinity complex. Following the formation of the heterodimer, the Toll-IL-1 receptor (TIR) domains approximate triggering the binding of MyD88, phosphorylations of the four IRAKs, TRAF-6, and activation of NFκB. The IL-18BP is present in the extracellular compartment where it binds mature IL-18 and prevents binding to the IL-18 receptor.
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