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Clin Exp Immunol. Jun 2004; 136(3): 402–404.
PMCID: PMC1809042

Interleukin-18 as a potential target in inflammatory arthritis

To date, the mechanisms underlying the aetiology of rheumatoid arthritis (RA) remain poorly understood. However, targeting tumour necrosis factor (TNF)-α in the clinic represents an exciting and important advance, in both therapeutics and understanding of disease pathogenesis. Non-responder or partial responder patients are not uncommon and disease usually flares on discontinuation of treatment [1]. Thus novel, pathogenesis-led interventions are required. Our group has studied cytokine networks in RA synovial membrane, identifying pathways regulating T lymphocyte function and TNF-α production that result in inflammatory synovitis. Interleukin (IL)-18, a member of the interleukin-1 cytokine superfamily, recognized as an important regulator of both innate and acquired immunity, is one such cytokine. We identified IL-18 expression within the inflamed synovium of RA patients [2] and similar reports document its presence in other autoimmune and chronic inflammatory diseases, in cancers and in numerous infectious diseases. This editorial will review function and focus on recent data including an article in this issue of Clinical and Experimental Immunology in which Ye and colleagues [3] provide data supporting a role for IL-18 in the induction and perpetuation of chronic inflammation during experimental and clinical RA. Activities in additional disease states and during infection have been discussed recently elsewhere [46].

IL-18 was originally termed interferon (IFN)-γ inducing factor (IGIF), an endotoxin-induced serum factor that stimulated IFN-γ production [7]. Involved in a variety of early inflammatory responses, IL-18 is present in many haemopoietic and non-haemopoietic cells [4]. IL-18 produced as a 24 kDa inactive precursor is cleaved by IL-1β converting enzyme (ICE, caspase-1) to generate a biologically active mature 18 kDa moiety [8,9]. Proteinase 3 (PR3) also generates biological activity from pro-IL-18 [10], and we have observed that the serine proteases, elastase and cathepsin G from human neutrophils may also generate novel IL-18-derived species. (unpublished data). The biological and functional significance of the latter remains unclear but neutrophil activation during early responses may regulate the ability of IL-18 to contribute to the phenotype of subsequent adaptive immune responses. Like IL-1β, the release of IL-18 from cells involves the purinergic receptor P2X-7 which, when triggered by ATP, results in pore formation in the plasma membrane [5,11]. For function, mature IL-18 binds a heterodimeric cell surface receptor (IL-18R). This comprises an α (IL-1Rrp) chain responsible for extracellular binding of IL-18 and a non-binding, recruited, signal transducing β (AcPL) chain [12,13]. This high-affinity complex induces signalling pathways shared with other IL-1R family members (e.g. TLRs) including recruitment and activation of myeloid differentiation 88 (MyD88) and IL-1R-associated kinase (IRAK) to the receptor complex [14]. IL-18R expressed on a variety of cells including macrophages, neutrophils, NK cells, endothelial and smooth muscle cells [4,15] can be up-regulated on naive T cells, Th1 type cells and B cells by IL-12. In contrast, T cell receptor (TCR) ligation together with IL-4 down-regulates IL-18R [16]. IL-18Rα serves as a stable marker of mature Th1 cells and anti-IL-18Rα antibody in vivo reduces lipopolysaccharide (LPS)-induced mortality associated with a subsequent shift in balance from a Th1 to a Th2 immune response [17].

Consistent effects by IL-18 on lymphoid series cells, particularly Th1 lineage in combination with IL-12, have emerged [18]. T and NK cell maturation, cytokine production and cytotoxicity as well as increasing FasL on NK cells and consequent Fas-FasL-mediated cytotoxicity are enhanced by IL-18 [16,1820]. IL-18 deficient mice have reduced NK cytolytic ability that can be restored by exogenous IL-18 [21]. However, together with IL-2, IL-18 co-induces IL-13 in murine T and NK cells and induces T cell IL-4, IL-10, IL-13 and IFN-γ production following TCR activation [22]. In isolation IL-18 induces high IgE expression by B cells and in combination with IL-2, anti-CD3 and anti-CD28 markedly enhances IL-4 production by CD4+ T cells [23]. When cultured alone or in combination with IL-4, IL-18 is known to induce murine T cell Th2 differentiation dependent upon strain [24]. Thus genetic influences and cytokine milieu can influence either Th1 or Th2 lineage maturation. Beyond T cell populations, IL-18 has direct effects on chondrocytes and cartilage matrix degradation [25].

IL-18 binding protein (IL-18 BP), a constitutively secreted protein that binds mature IL-18 with high affinity, provides a potential mechanism to regulate IL-18 activity. It inhibits IL-18 induced IFN-γ and, IL-8 production and NFκB activation in vitro and LPS-induced IFN-γ production in vivo[26]. Inhibition of IFN-γ production in turn augments peripheral blood mononuclear cells (PBMC) prostaglandin production. The existence of an endogenous IFN-γ regulated feedback loop is suggested, as IL-18 BP expression may itself be augmented by IFN-γ and levels of IL-18 BP are increased during sepsis and in endothelial cells and macrophages during active Crohn's disease [27]. The recent discovery of IL-1H, a protein with sequence homology to IL-1ra, able to bind the IL-18R but not IL-1R suggests the existence of further IL-18R antagonism in vivo[28].

IL-18 expression is up-regulated in RA and psoriatic arthritis synovial membrane and levels are raised in serum and synovial fluids of these patients ([2,29] and our unpublished observations). Although 24 kDa pro-IL-18 predominates, mature IL-18 is consistently detected. Expression is localized in macrophages and in fibroblast-like synoviocytes (FLS) in situ. IL-18Rα and β chains are detected ex vivo on synovial CD3+ lymphocytes and synovial CD14+ macrophages and in vitro on FLS. IL-18 BP may also be present in substantial concentrations [30]. Within the synovium, IL-18, in marked synergy with IL-12 and IL-15, promotes cytokine release (particularly TNF-α, granulocyte-macrophage colony stimulating factor (GM-CSF) and IFN-γ) [4]. Addition of recombinant IL-18 to cytokine-activated, formalin-fixed synovial T cell/monocyte cocultures synergistically up-regulates TNF-α production showing that in addition to lymphocyte activation, IL-18 can act in an autocrine fashion upon the monocyte population (unpublished observations). Intracellular FACS staining of macrophages following IL-18 addition shows up-regulated TNF-α expression further supporting such feedback loops [2]. Dose–response studies reveal that very low concentrations (as little as 1 pg/ml) of IL-18 in synergy with IL-15 will induce significant TNF-α production in vitro[4].

IL-18 expression is up-regulated in turn in FLS by IL-1β and TNF-α, suggesting the existence of positive feedback loops linking monokine predominance in RA with innate cytokine production and Th/c 1 cell activation in synovial immune responses. NO which inhibits caspase-1 activity, is up-regulated in RA SM in vitro by IL-18, suggesting a further potential regulatory loop. IL-18 possesses pro-degradative effects in articular cartilage by reducings chondrocyte proliferation, up-regulating iNOS, stromelysin and cyclooxygenase 2 expression and increasing glycosaminoglycan (GAG) release. Such activities may be IL-1β independent, although contradictory data have also emerged [31]. IL-18 promotes neutrophil activation, reactive oxygen intermediate synthesis, cytokine release and degranulation [2,15]. IL-18 further promotes synovial chemokine synthesis and angiogenesis as well as up-regulation of intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expression on endothelial cells and synovial fibroblasts [32]. Finally, IL-18 effects are not necessarily detrimental, as it inhibits osteoclast maturation through GM-CSF production by T cells, thereby retarding bone erosion [33]. Suppression of COX expression may also be mediated through IFN-γ production with consequent effects upon prostanoid-mediated local inflammation. The pleiotropic effects of IL-18 on promoting the inflammatory response in inflammatory arthritis is shown in Fig. 1.

Fig. 1
Pleiotropic effects of IL-18 in promotion of inflammatory arthritis. Numerous approaches are now being developed to target IL-18 in the clinic.

Several arthritis models have targeted IL-18 in vivo. IL-18-deficient mice exhibit reduced incidence and severity of arthritis in a collagen (CII)-induced arthritis (CIA) model. Both cellular and humoral responses to CII are suppressed [34,35]. Using specific anti-IL-18 antibodies or IL-18 BP effectively reduces developing and established rodent arthritis in both streptococcal cell wall and CIA models [31,36,37]. Such effects may operate independently of IFN-γ[31]. In both models joint destruction as well as inflammation is halted. These data strongly suggest a proinflammatory role for IL-18 in the context of antigen-driven articular inflammation. In this current issue, Ye adds to this evidence using a rat model of CIA [3]. Treatment with low doses of IL-18 prior to induction of disease using a ‘low potency’ model was able to increase both incidence and severity of the disease. In addition proinflammatory cytokines were increased by the IL-18 treatment. This confirms similar work in our laboratory, where IL-18 enhanced disease in a less aggressive murine model [35]. Interestingly, Ye has found that very high doses of IL-18 appeared to inhibit disease, an observation worthy of further investigation. Their neutralization studies using antibody therapy also suggest that the pro-arthritic effects of IL-18 could be attenuated. Administration either at time of immunization or later in the model but before disease onset was able to reduce both disease incidence and severity. This study, however, did not directly examine the possibility of improving outcome by delaying the antibody treatment until after clinical signs of disease, i.e. equivalent of therapeutic treatment in the clinical setting.

In summary, IL-18 therefore represents an exciting novel inflammatory mediator that is up-regulated in numerous clinical situations including autoimmune rheumatic diseases and represents a novel therapeutic target. Clinical studies to test this hypothesis in RA are currently ongoing using specific biological agents capable of targeting IL-18, including anticytokine antibodies and recombinant soluble IL-18 BP. Future approaches may include attempting to block cytokine release from the cell (e.g. P2X-7 blockade), enzyme blockade (e.g. ICE) to prevent the formation of active IL-18 and the use of novel IL-18 species to antagonize cytokine/receptor interactions (Fig. 1).

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