Abstract
Interleukin 18 (IL-18) is a pro-inflammatory cytokine of the IL-1 family, whose activity is tightly controlled at the level of production, as well as signalization. Notably, it is buffered by its natural inhibitor, IL-18 binding protein (IL-18BP), which is massively present in circulation in normal and in most pathological conditions, thus preventing harmful pro-inflammatory systemic effects of IL-18. IL-18 has long been considered to be involved in the pathophysiology of various inflammatory diseases. However, a first clinical trial using recombinant IL-18BP for the treatment of rheumatoid arthritis and psoriasis gave disappointing results. Direct measurements of unbound, bioactive, free form of circulating IL-18 demonstrated that IL-18 was more specifically involved in adult-onset Still’s disease (AOSD) and systemic juvenile idiopathic arthritis (sJIA) but also in their most severe complication, macrophage activation syndrome (MAS). More importantly, administration of recombinant IL-18BP to patients with AOSD, and sJIA with MAS, showed promising results. This review summarizes available data regarding IL-18 and IL-18BP in AOSD and sJIA in mouse models and humans and shows the importance of IL-18/IL-18BP imbalance in these conditions, leading to the conclusion that IL-18, particularly free IL-18, may be a useful biomarker in these diseases and an interesting therapeutic target.
Highlights
Among other biological markers, interleukin 18 (IL-18) appears as a reasonable candidate for a better understanding of adult-onset Still’s disease (AOSD) and systemic juvenile idiopathic arthritis pathophysiology, evaluation of disease activity, and therapeutic approaches
High circulating levels of IL-18 have been measured in a large number of inflammatory diseases [21,29,30,31,32,33,34], and IL-18 has been shown to be overexpressed in affected organs, such as the intestinal mucosa in Crohn’s disease, the synovial tissue in rheumatoid arthritis, and the skin lesions in psoriasis [35,36,37]
We showed that IL-18 binding protein (IL-18BP)-deficient mice displayed a more severe phenotype than wild-type (WT) animals and that this was associated with the detection of circulating free IL-18 in IL-18BP-deficient but not in WT mice
Summary
Interleukin 18 (IL-18) appears as a reasonable candidate for a better understanding of adult-onset Still’s disease (AOSD) and systemic juvenile idiopathic arthritis (sJIA) pathophysiology, evaluation of disease activity, and therapeutic approaches. We will make a brief presentation of IL-18 and IL-18 binding protein (IL-18BP) biology, summarize the fundamental and translational work that has been conducted in the last two decades in this topic, and, state how IL-18 and IL-18BP could be used in clinical practice, for the management of AOSD and sJIA. 2. Interleukin 18, Interleukin 18-Binding Protein, and the Interleukin 18/Interleukin
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