Interleukin-18 and IL-18 Binding Protein

Charles A Dinarello,Soohyun Kim,Daniela Novick,Gilles Kaplanski

doi:10.3389/fimmu.2013.00289

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.

Highlights

TO IL-18 Interleukin-18 (IL-18) was first described in 1989 as “IFNγinducing factor” isolated in the serum of mice following an intraperitoneal injection of endotoxin
Similar observations were made in mice [5]. These findings suggest that IL-18 may act as regulator of homeostasis
If one examines immunologically mediated diseases where IFNγ plays a pathological role such as Wegener’s granulomatosis and systemic lupus erythematosus, one must consider the level of free IL-18 compared to IL-18 bound to IL-18 binding protein (IL-18BP)

Summary

Introduction

TO IL-18 Interleukin-18 (IL-18) was first described in 1989 as “IFNγinducing factor” isolated in the serum of mice following an intraperitoneal injection of endotoxin. 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 most cells in healthy humans and animals. 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.

Results

Conclusion