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Interleukin-18, rheumatoid arthritis, and tissue destruction
Jean-Michel Dayer
Division of Immunology and Allergy, University Hospital, 1211 Geneva 14, Switzerland.
Phone: 41-22-372-9409; Fax: 41-22-372-9418; E-mail: Jean-Michel.Dayer@hcuge.ch or Jean-Michel.Dayer@medecine.unige.ch.
Find articles by Dayer, J. in: JCI | PubMed | Google Scholar
Published November 15, 1999 - More info
J Clin Invest. 1999;104(10):1337–1339. https://doi.org/10.1172/JCI8731.
© 1999 The American Society for Clinical Investigation
In this issue of the JCI, J. Alastair Gracie et al. highlight the central importance of IL-18 among several novel cytokines that participate in erosive, inflammatory arthritis (1). The authors base their arguments on experimental results obtained in vitro with human synovial tissue and in vivo with mice immunized with collagen in the presence of incomplete Freund’s adjuvant.
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IL-18 in human disease.
IL-18 mRNA appears to be widely, but not ubiquitously, expressed (4). Based on the results of Gracie et al. in this issue of the JCI, inflamed synovial tissue, particularly in rheumatoid arthritis, can now be added to the list of tissues that express this factor. IL-18 is found primarily in lymphocytic aggregates, but its precise localization remains unclear.
Roles for IL-18 in various pathological conditions are currently of great interest. Figure 1 summarizes several of IL-18’s emerging functions in promoting or suppressing disease. In infectious diseases, IL-18 plays a crucial part in promoting the inflammatory response during bacterial sepsis, a response that can lead to hepatic injury and multiple organ failure (2). On the other hand, like many proinflammatory cytokines, IL-18 appears to act in host defense. For example, in one report, pretreatment with IL-18 prevented or minimized the severity of experimentally induced bacterial infection (10). Therapies that target IL-18 must therefore be approached with caution, because of their possible effects on IFN-γ and hence on the control of intracellular pathogens by macrophages. IL-18 is also instrumental in the suppression of allergy, because it inhibits IgE production (11). With regard to type 1 diabetes, IL-18 favors the development of insulitis in nonobese diabetic mice. Furthermore, the mouse IL-18 gene maps near the Idd2 interval, raising the possibility that recessive defects in the IL-18 gene (along with at least 2 other interacting genes) contribute to the nonobese diabetic phenotype (12). However, in other studies, IL-18 was shown to decrease insulitis (13).
Figure 1Potential roles for IL-18 in various pathological conditions. Yellow highlighting indicates a potentially beneficial effect of IL-18.
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IL-18 in rheumatoid arthritis.
The observations of Gracie et al. in this issue of the JCI indicate that IL-18 may play an additional pathogenic role in rheumatoid arthritis, a disease that is driven by Th1 responses. IL-18 appears to synergize with IL-12 and IL-15 to activate production by synovial tissue of IFN-γ and of IL-18 itself. Three observations are noteworthy. First, GM-CSF and NO production by macrophages is induced by IL-18 and is not dependent on IL-12 and IL-15. This contrasts with the synergism of these 3 cytokines in regulating TNF-α production. Second, a counter-regulatory loop may exist through NO production, because NO inhibits the IL-1β–converting enzyme (ICE) and thus blocks the processing of proIL-18 into a biologically active cytokine. Thus, by inducing NO, IL-18 decreases its own activity. Third, IL-18 production by synovial tissue is upregulated by TNF-α and IL-1β.
The local activation of monocyte-macrophages leads to the production of IL-1, TNF-α, and matrix metalloproteinases (MMPs) in the inflammatory lesion. This activation is mediated by cytokines and immune complexes, but primarily by cell-cell contact with activated T cells or synovial cells (14–16). Like IL-15, IL-18 may potentiate cell-cell contact in inflamed tissue, such as synovia in rheumatoid arthritis.
A recent study identified active ICE in human articular cartilage (17). ICE was markedly increased in osteoarthritic tissue, and led to the production of both active IL-1β and IL-18. The increased production of IL-18 in synovia from patients with rheumatoid arthritis and in mucosal intestinal tissue in Crohn’s disease has also been reported (18, 19). It has always been surprising that relatively low IFN-γ levels should be detected in rheumatoid arthritis synovitis, despite the presence of Th1 cells. One explanation, proposed by Gracie et al., holds that IL-18 sustains the Th1 phenotype without inducing persistently high levels of IFN-γ production because inhibitory molecules, such as IL-10 and TGF-β, are also highly expressed.
The present report agrees with another recent study (20) that shows that IL-18 induces proinflammatory and catabolic responses in normal human cartilage. Although these findings provide a rationale for blocking IL-18 in treating rheumatoid arthritis, the beneficial effects of this cytokine, shown in Table 1, justify caution. In addition to its above-described roles in host defense and the suppression of allergies, IL-18 induces NO, which can block ICE activity. Therefore, inhibition of IL-18 function could increase ICE activity and promote the maturation of IL-18 and IL-1β, thereby promoting the inflammation and tissue destruction that one is attempting to control. Moreover, IL-18 may inhibit osteoclast formation (21), so blocking IL-18 activity may have long-term effects on bone metabolism, perhaps causing osteoporosis.
The dilemma regarding the role of this cytokine persists: Does IL-18 protect tissues from infection, or does it mediate deleterious effects during sepsis? Its roles in acute or chronic inflammatory conditions and in long-term physiological tissue remodeling are ambiguous. Careful monitoring of relevant biological markers is necessary, even in phase I and phase II clinical trials, to avoid undesirable long-term consequences of therapies that seek to suppress the activity of this pleiotropic factor.
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