• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of clinexpimmunolLink to Publisher's site
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 (unpublished data).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).


1. Lipsky PE, van der Heijde DM, St Clair EW, et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. N Engl J Med. 2000;343:1594–602. [PubMed]
2. Gracie JA, Forsey RJ, Chan WL, et al. A proinflammatory role for IL-18 in rheumatoid arthritis. J Clin Invest. 1999;104:1393–401. [PMC free article] [PubMed]
3. Ye XJ, Tang B, Ma Z, et al. The role of interleukin-18 in collagen-induced arthritis in the BB rat. Clin Exp Immunol. 2004;136:440–7. [PMC free article] [PubMed]
4. Gracie JA, Robertson SE, McInnes IB. Interleukin-18. J Leukoc Biol. 2003;73:213–24. [PubMed]
5. Dinarello CA, Fantuzzi G. Interleukin-18 and host defense against infection. J Infect Dis. 2003;187(Suppl. 2):S370–84. [PubMed]
6. Nakanishi K, Yoshimoto T, Tsutsui H, Okamura H. Interleukin-18 regulates both Th1 and Th2 responses. Annu Rev Immunol. 2001;19:423–74. [PubMed]
7. Nakamura K, Okamura H, Wada M, Nagata K, Tamura T. Endotoxin-induced serum factor that stimulates gamma interferon production. Infect Immun. 1989;57:590–5. [PMC free article] [PubMed]
8. Ghayur T, Banerjee S, Hugunin M, et al. Caspase-1 processes IFN-gamma-inducing factor and regulates LPS-induced IFN-gamma production. Nature. 1997;386:619–23. [PubMed]
9. Gu Y, Kuida K, Tsutsui H, et al. Activation of interferon-gamma inducing factor mediated by interleukin-1beta converting enzyme. Science. 1997;275:206–9. [PubMed]
10. Sugawara S, Uehara A, Nochi T, et al. Neutrophil proteinase 3-mediated induction of bioactive IL-18 secretion by human oral epithelial cells. J Immunol. 2001;167:6568–75. [PubMed]
11. Mehta VB, Hart J, Wewers MD. ATP-stimulated release of interleukin (IL)-1beta and IL-18 requires priming by lipopolysaccharide and is independent of caspase-1 cleavage. J Biol Chem. 2001;276:3820–6. [PubMed]
12. Torigoe K, Ushio S, Okura T, et al. Purification and characterization of the human interleukin-18 receptor. J Biol Chem. 1997;272:25737–42. [PubMed]
13. Born TL, Thomassen E, Bird TA, Sims JE. Cloning of a novel receptor subunit, AcPL, required for interleukin-18 signaling. J Biol Chem. 1998;273:29445–50. [PubMed]
14. Adachi O, Kawai T, Takeda K, et al. Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function. Immunity. 1998;9:143–50. [PubMed]
15. Leung BP, Culshaw S, Gracie JA, et al. A role for IL-18 in neutrophil activation. J Immunol. 2001;167:2879–86. [PubMed]
16. Yoshimoto T, Takeda K, Tanaka T, et al. IL-12 up-regulates IL-18 receptor expression on T cells, Th1 cells, and B cells: synergism with IL-18 for IFN-gamma production. J Immunol. 1998;161:3400–7. [PubMed]
17. Xu D, Chan WL, Leung BP, et al. Selective expression and functions of interleukin 18 receptor on T helper (Th) type 1 but not Th2 cells. J Exp Med. 1998;188:1485–92. [PMC free article] [PubMed]
18. Okamura H, Tsutsi H, Komatsu T, et al. Cloning of a new cytokine that induces IFN-gamma production by T cells. Nature. 1995;378:88–91. [PubMed]
19. Micallef MJ, Ohtsuki T, Kohno K, et al. Interferon-gamma-inducing factor enhances T helper 1 cytokine production by stimulated human T cells: synergism with interleukin-12 for interferon-gamma production. Eur J Immunol. 1996;26:1647–51. [PubMed]
20. Dao T, Mehal WZ, Crispe IN. IL-18 augments perforin-dependent cytotoxicity of liver NK-T cells. J Immunol. 1998;161:2217–22. [PubMed]
21. Takeda K, Tsutsui H, Yoshimoto T, et al. Defective NK cell activity and Th1 response in IL-18-deficient mice. Immunity. 1998;8:383–90. [PubMed]
22. Hoshino T, Wiltrout RH, Young HA. IL-18 is a potent coinducer of IL-13 in NK and T cells: a new potential role for IL-18 in modulating the immune response. J Immunol. 1999;162:5070–7. [PubMed]
23. Yoshimoto T, Mizutani H, Tsutsui H, et al. IL-18 induction of IgE: dependence on CD4+ T cells, IL-4 and STAT6. Nat Immunol. 2000;1:132–7. [PubMed]
24. Xu D, Trajkovic V, Hunter D, et al. IL-18 induces the differentiation of Th1 or Th2 cells depending upon cytokine milieu and genetic background. Eur J Immunol. 2000;30:3147–56. [PubMed]
25. Olee T, Hashimoto S, Quach J, Lotz M. IL-18 is produced by articular chondrocytes and induces proinflammatory and catabolic responses. J Immunol. 1999;162:1096–100. [PubMed]
26. Novick D, Kim SH, Fantuzzi G, Reznikov LL, Dinarello CA, Rubinstein M. Interleukin-18 binding protein: a novel modulator of the Th1 cytokine response. Immunity. 1999;10:127–36. [PubMed]
27. Corbaz A, ten Hove T, Herren S, et al. IL-18-binding protein expression by endothelial cells and macrophages is up-regulated during active Crohn's disease. J Immunol. 2002;168:3608–16. [PubMed]
28. Pan G, Risser P, Mao W, et al. IL-1H, an interleukin 1-related protein that binds IL-18 receptor/IL-1Rrp. Cytokine. 2001;13:1–7. [PubMed]
29. Yamamura M, Kawashima M, Taniai M, et al. Interferon-gamma-inducing activity of interleukin-18 in the joint with rheumatoid arthritis. Arthritis Rheum. 2001;44:275–85. [PubMed]
30. Kawashima M, Miossec P. Heterogeneity of response of rheumatoid synovium cell subsets to interleukin-18 in relation to differential interleukin-18 receptor expression. Arthritis Rheum. 2003;48:631–7. [PubMed]
31. Lubberts E, van den Berg WB. Potential of modulatory cytokines in the rheumatoid arthritis process. Drug News Perspect. 2001;14:517–22. [PubMed]
32. Morel JC, Park CC, Zhu K, Kumar P, Ruth JH, Koch AE. Signal transduction pathways involved in rheumatoid arthritis synovial fibroblast interleukin-18-induced vascular cell adhesion molecule-1 expression. J Biol Chem. 2002;277:34679–91. [PubMed]
33. Horwood NJ, Udagawa N, Elliott J, et al. Interleukin 18 inhibits osteoclast formation via T cell production of granulocyte macrophage colony-stimulating factor. J Clin Invest. 1998;101:595–603. [PMC free article] [PubMed]
34. Wei XQ, Leung BP, Arthur HM, McInnes IB, Liew FY. Reduced incidence and severity of collagen-induced arthritis in mice lacking IL-18. J Immunol. 2001;166:517–21. [PubMed]
35. Leung BP, McInnes IB, Esfandiari E, Wei XQ, Liew FY. Combined effects of IL-12 and IL-18 on the induction of collagen-induced arthritis. J Immunol. 2000;164:6495–502. [PubMed]
36. Plater-Zyberk C, Joosten LA, Helsen MM, et al. Therapeutic effect of neutralizing endogenous IL-18 activity in the collagen-induced model of arthritis. J Clin Invest. 2001;108:1825–32. [PMC free article] [PubMed]
37. Smeets RL, Van De Loo FA, Arntz OJ, Bennink MB, Joosten LA, Van Den Berg WB. Adenoviral delivery of IL-18 binding protein C ameliorates collagen-induced arthritis in mice. Gene Ther. 2003;10:1004–11. [PubMed]

Articles from Clinical and Experimental Immunology are provided here courtesy of British Society for Immunology
PubReader format: click here to try


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • Compound
    PubChem Compound links
  • PubMed
    PubMed citations for these articles
  • Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...