Elsevier

Seminars in Immunology

Volume 25, Issue 6, 15 December 2013, Pages 439-448
Seminars in Immunology

Review
Interleukin-18, more than a Th1 cytokine

https://doi.org/10.1016/j.smim.2013.10.014Get rights and content

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.

Section snippets

Introduction to IL-18

IL-18 was first described in 1989 as “IFNγ-inducing factor” isolated in the serum of mice following an intraperitoneal injection of endotoxin. Days before, the mice had been pretreated with Proprionibacterium acnes, which stimulates the reticuloendothelial system, particularly the Kupffer cells of the liver. Many investigators concluded that the serum factor was IL-12. With purification from mouse livers and molecular cloning of “IFNγ-inducing factor” in 1995 [1], the name was changed to IL-18.

Processing of the IL-18 precursor by caspase-1

The IL-18 precursor has a molecular weight of 24,000 and is processed by the intracellular cysteine protease caspase 1, which cleaves the precursor into an active mature molecule of 17,200. As with the processing of IL-1β, inactive pro-caspase-1 is first converted into active caspase-1 by the nucleotide-binding domain and leucine-rich repeat pyrin containing protein-3 (NLRP3) inflammasome. Following cleavage of the IL-18 precursor by active caspase-1, mature IL-18 is secreted from the

Role of IL-18 in the production of IFNγ

Together with IL-12, IL-18 participates in the Th1 paradigm. This property of IL-18 is due to its ability to induce IFNγ either with IL-12 or IL-15. Without IL-12 or IL-15, IL-18 does not induce IFNγ. IL-12 or IL-15 increases the expression of IL-18Rβ, which is essential for IL-18 signal transduction. Importantly, without IL-12 or IL-15, IL-18 plays a role in Th2 diseases [27]. The importance of IL-18 as an immunoregulatory cytokine is derived from its prominent biological property of inducing

Proinflammatory properties of IL-18

In the absence of IL-12 or IL-15, IL-18 exhibits characteristics of other proinflammatory cytokines of the IL-1 family, such as increases in cell adhesion molecules, nitric oxide synthesis, and chemokine production. Table 1 lists the disease models in which inhibition of IL-18 activity by administration of either neutralizing anti-IL-18 antibodies or the IL-18 binding protein has been reported. In general, inhibition of IL-18 activity results in a reduction in disease severity. Table 2 lists

IL-18 as a protective cytokine

As stated above, mice deficient in caspase-1 experience increased disease severity when subjected to DSS colitis and that administration of exogenous IL-18 restored mucosal healing in these mice [59]. In addition, IL-18 deficiency or IL-18 receptor deficiency results in the development of a metabolic syndrome in mice. Mice deficient in NLRP3 are more susceptible to DSS colitis, which is thought to be due to decreased IL-18 [60]. Mice deficient in NLRP6 are also more vulnerable to DSS [61], [62]

The discovery of the IL-18BP

The discovery of the IL-18BP took place during the search for the soluble receptors for IL-18 [76]. IL-18BP is a constitutively secreted protein, with an exceptionally high affinity for IL-18 (400 pM) [159] (Fig. 1). Present in the serum of healthy humans at a 20-fold molar excess compared to IL-18 [77], IL-18BP may contribute to a default mechanism by which a Th1 response to foreign organisms is blunted in order to reduce triggering an autoimmune responses to a routine infection. IL-18BP

Hemophagocytic lympho-histiocytosis and macrophage activation syndrome

Hemophagocytic lympho-histiocytosis syndrome (HLH) is a rare life-threatening condition characterized by a severe hyper-inflammatory state. There is a genetic form of HLH called familial hemophagocytic lympho-histiocytosis (fHLH). However, HLH can be secondary to infections and lymphoma, and is called secondary macrophage activation syndrome (MAS). The development of MAS is associated with several infectious diseases, notably due to Epstein-Barr Virus, cytomegalovirus, herpes virus or

Acknowledgements

These studies are supported by NIH AI-15614, AR-45584 and CA-04 6934 (to CAD) and Agence Nationale de la Recherche-Maladies Rares 2007 et Projet National de Recherche Clinique 2007 (to GK). Soohyun Kim is supported by the National Research Foundation of Korea (MEST: 2012R1A2A1A01001791) and the Konkuk University research support program.

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