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CRITICAL REVIEWS IN ORAL BIOLOGY & MEDICINE |
Interleukin 18 and Periodontal Disease
A. Orozco1,*,
E. Gemmell1,
M. Bickel1 and
G.J. Seymour2
1 School of Dentistry, Turbot Street, Brisbane 4000, Australia; and
2 Faculty of Dentistry, University of Otago, Dunedin, New Zealand
Correspondence: * corresponding author, orozco{at}bigpond.net.au
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ABSTRACT
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Cytokines are of major importance in periodontal disease progression. It is generally agreed that control of the Th1/Th2 balance is central to the immunoregulation of periodontal disease. There is increasing evidence in humans that the stable periodontal lesion is mediated by Th1 cells, while the progressive lesion sees a shift toward Th2 cells. Equally, there is conflicting evidence, mainly in animal models, that bone loss is mediated by Th1 responses, and that Th2 responses are protective. In the presence of IL-12, IL-18 induces Th1 responses while, in the absence of IL-12, it promotes Th2 responses. It is clear, therefore, that since IL-18 has the ability to induce either Th1 or Th2 differentiation, it becomes important to consider its role in periodontal disease. This review endeavors to give an overview of this cytokine and its relevance for periodontal disease.
Key Words: periodontitis • gingivitis • cytokines • IL-18
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INTRODUCTION
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Cytokines are central to the pathogenesis of an ever-increasing number of diseases, including periodontal disease. They are inter-cellular messengers and, as such, represent a key mechanism by which cells involved in immune responses communicate. Numerous cytokines are produced in response to microbes and other antigens and stimulate diverse responses. Cells that produce cytokines include the macrophages/monocytes, dendritic cells, lymphocytes, neutrophils, endothelial cells, and fibroblasts (Abbas and Lichtman, 2003). They are usually produced transiently, often in picomolar concentrations, and some, such as interleukin (IL)-4, may have a very restricted range of activity. Indeed, the majority of immune responses occur locally, and often between two cells conjugated together. In other situations, however, large amounts of cytokine are produced, which allows cells to communicate at a distance (Seymour and Taylor, 2004). Such cytokines include IL-1 and IL-6, which are produced by a large number of cells and in relatively large quantities. Cytokines interact in a network by inducing each other, transmodulating cell-surface receptors, and by synergistic, additive, or antagonistic interactions on cell function (Balkwill and Burke, 1989).
In periodontal disease, cytokines are central. It has been postulated that "appropriate" cytokine production results in protective immunity, while "inappropriate" cytokine production leads to tissue destruction and disease progression (Gemmell and Seymour, 2004). Cytokines have a tremendous built-in redundancy, such that many cytokines have overlapping functions. Equally, many cytokines are antagonistic, and, again, the overall biological effect is the result of the balance between all cytokines, rather than their individual levels. The balance between cellular and humoral responses, for example, is strongly regulated by the balance between Th1 and Th2 subsets. These T-cell subsets have contrasting cytokine profiles (Mosmann and Sad, 1996). Th1 cells are characterized by their production of interferon- (IFN-) and are responsible for directing cell-mediated immune responses leading to the eradication of intracellular pathogens, but may also cause immunopathology and organ-specific autoimmune disease if dysregulated (O’Garra, 1998). Several cytokines are involved in Th1 immune responses. These include: IL-12, IL-18, IFN-, and tumor necrosis factor (TNF)- . In contrast, IL-4, IL-5, and IL-13 are involved in Th2 immune responses and promote humoral immunity by promoting B-cell growth and differentiation (Mosmann and Sad, 1996; Belardelli and Ferrantini, 2002). It is generally agreed that control of the Th1/Th2 balance is central to the immunoregulation of periodontal disease (Seymour and Taylor, 2004). In turn, this balance is controlled by several factors, including genetics, the nature of antigen(s), the nature of the antigen-presenting cell, the innate immune response, and T-cell receptor interactions. It has also been suggested that the stable periodontal lesion is mediated by Th1 cells, while the progressive lesion sees a shift toward Th2 cells (Seymour and Gemmell, 2001; Gemmell and Seymour, 2004).
IL-18 was first discovered in 1995 by Okamura et al. (Okamura et al., 1995), and was originally identified as interferon- (IFN-)-inducing factor. IL-18 is a pro-inflammatory and tumor-suppressive cytokine, which, due to its structure, receptor family, and signal transduction pathways, belongs to the IL-1 cytokine family (Biet et al., 2002; Muhl and Pfeilschifter, 2004). It is unique, with the capacity to induce either Th1 or Th2 differentiation, depending on the immunological context (Nakanishi et al., 2001a). The last few years have seen an outburst of studies exploring various aspects of this unique cytokine, although its role in periodontal disease has received relatively scant attention.
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PRODUCTION, STRUCTURE, GENERATION, RECEPTORS, AND BIOLOGICAL EFFECTS OF IL-18
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The human IL-18 gene is located on chromosome 11q22; the synthesized protein contains 193 amino acids and shares 64% identity with its mouse homologue (Nolan et al., 1998).
Although the IL-1 family members—IL-1, IL-1β, and IL-1 receptor antagonist (IL-1Ra)—share less than 30% primary amino acid sequence homology, they display structural similarities (Biet et al., 2002). While IL-1 and IL-18 and their receptors are members of the IL-1 family, there are several biological and functional differences among them. One of these is that IL-18 induces IFN- from T-cells and NK cells, but does not cause fever, whereas induction of fever is a well-known characteristic of IL-1β (Li et al., 2003).
Kato et al.(2003), using MNR spectroscopy, have described the IL-18 structure. Its overall structure is well-defined, except the segment between residues 34 and 43. IL-18 consists of 12 strands that form 3 twisted four-stranded β-sheets, with one short -helix and one 310-helix. The three β-sheets are packed against each other, to adopt a β-trefoil fold, which is similar to those of IL-1β, but the surface residues are totally dissimilar. The loop, residues 32–42, spreads out from the body of the protein and seems to be flexible. Kato et al.(2003) further described 3 sites important for receptor activation: 2 that serve as binding sites for IL-18R(), and the third for binding to IL-18R(β).
IL-18 receptor (IL-18R) is found on T-cells, NK cells, B-cells, and dendritic cells (Sigal, 2005). It shares structural organization with the IL-1R/Toll-like receptor (TLR) superfamily. The IL-18 receptor (IL-18RC) complex consists of 2 receptor chains: the ligand-binding IL-18R chain, originally identified as IL-1 receptor-related protein (IL-1Rrp), and the core-receptor IL-18Rβ chain, formerly designated as accessory-protein-like (IL-18AcPL). Both chains are required for signaling. The activity of IL-18 begins with its binding to the IL-18RC. IL-18R binds IL-18 with low affinity, whereas IL-18Rβ does not bind IL-18, but increases the affinity of the receptor and participates in signal transduction (Born et al., 1998).
The mechanism by which the formation of the IL-18RC leads to intracellular signal transduction is exemplified in Fig. 1 . The recognition of glycosylphosphatidylinositol (GPI) anchor glycans by IL-18 and IL-18R induces formation of the IL-18/IL-18R/CD48/GPI anchor glycan complex, and this complex and the specific peptide sequences trigger binding to IL-18Rβ and induce intracellular signal transduction (Fukushima et al., 2005).
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Figure 1. Signal transduction pathways of IL-18. Intracellular activation of caspase (caspase-1 or caspase-1-like enzymes) in antigen-presenting cells is mediated through Toll-like receptor (TLR) or Fas signaling, respectively. Caspase-1 and the extracellular serine esterase PR-3 induce activation of biologically active interleukin (IL)-18 (18 kDa) by cleavage of its precursor, pro-IL-18 (24 kDa). If not inactivated by the extracellular IL-18-binding protein (IL-18BP), processed mature IL-18 mediates IL-18RC aggregation (IL-18 receptor complex, consisting of IL-18Rl, IL-18, CD48, and GPI), which binds to IL-18Rβ, leading to signal transduction by recruiting myeloid differentiation factor (MyD88), as well as IL-1 receptor-associated kinase (IRAK) in the effector cell. After phosphorylation, IRAK dissociates from the receptor complex and associates with tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6), which then leads to sequential activation of NF-  B binding kinase (NIK), I-B kinases (IKK-1, IKK-2), and NF-B. Alternatively, the binding of IL-18 triggers the activation of Ras via a src family member of tyrosine kinases, the lymphocyte-specific tyrosine-specific protein kinase of 56 kDa (p56lck). Ras then sequentially activates Raf, mitogen-activated extracellular signal-regulated kinase-activating kinase (MEK) and mitogen-activated protein kinase (MAPK). This induces phosphorylation of MAPK, which is then translocated into the nucleus and phosphorylates CCAAT/enhancer-binding protein (C/EBP), enabling it to associate with the C/EBP binding site. Both NF-B and C/EBP induce gene transcription to produce further inflammatory mediators (such as IFN-, TNF-, IL-6, etc.). Adapted and modified from Tschoeke et al.(2006) and Fukushima et al.(2005).
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IL-18R has been reported to be selectively expressed on Th1, but not Th2, cells, and was proposed to be considered as a cell-surface marker to distinguish Th1 from Th2 cells (Parnet et al., 1996). Although Th2 cells expressing IL-18R have been reported (Tominaga et al., 2000), they cannot produce IFN- in response to anti-CD-3 and IL-18, whereas functional IL-18R is selectively expressed on Th1 and shows a strong capacity to produce IFN- in response to anti-CD-3 plus IL-18 or IL-1β (Tominaga et al., 2000). In this context, the mechanism by which IL-18 influences Th2 cells remains to be determined.
With regard to the B-cells, it has been found that human B-cell lines ubiquitously express mRNA for IL-18, IL-18R, and IL-18Rβ, but do not secrete IL-18 protein; hence, IL-18 possibly affects B-cells through paracrine actions, and it may well be that B-cells may be passive bystanders with an innate ability to use IL-18 (Lorey et al., 2004).
Similar to IL-1β, IL-18 is intracellularly synthesized as a 24-kDa biologically inactive precursor (pro-IL-18) (Ushio et al., 1996), and is secreted as an 18-kDa inactive form requiring caspase-1 (ICE) (which is the same enzyme that cleaves pro-IL-1β IL-1β-converting enzyme), to cleave it into the active IL-18 molecule (Ghayur et al., 1997; Gu et al., 1997; Dinarello, 1999; Fantuzzi and Dinarello, 1999; Opal and DePalo, 2000; Biet et al., 2002). This process could occur after Toll-like receptor-4 (TLR-4) is activated by lipopolysaccharide (LPS), or, alternatively, upon stimulation with FasL, a caspase other than ICE, termed ’casp1-like’, which might be activated to cleave the pro-IL-18 into active IL-18 (Nakanishi et al., 2001b). The pathways are explained in more detail below.
Following activation of pro-IL-18, active IL-18 mediates IL-18R aggregation, after which the heterodimeric complex recruits the adaptator molecule MyD88, as well as IL-1 receptor-associated kinase (IRAK). After phosphorylation, IRAK dissociates from the receptor complex and then associates with TNF receptor-associated factor 6 (TRAF6), which leads to the sequential activation of NF-B binding kinase (NIK), I-B kinases (IKK-1, IKK-2). This leads to the release of the NF-B subunits p65/p50 from I-B, and their translocation to the nuclear B-binding sites. Alternatively, the binding of IL-18 triggers the activation of Ras, resulting in an activation cascade of Raf, mitogen-activated extracellular signal-regulated kinase-activating kinase (MEK), and mitogen-activated protein kinase (MAPK). This induces phosphorylation of MAPK. After phosphorylation, MAPK is translocated into the nucleus and phosphorylates NF-IL6, which allows NF-IL6 to associate to the C/ERP binding site (Fig. 1 ) (Dinarello, 1999; Nakanishi et al., 2001b; Biet et al., 2002; Kashiwamura et al., 2002; Reddy, 2004).
In epithelial cells, IL-18 transduction is primarily via the MAPK p38 pathway, rather than NF-B, which may explain the absence of cyclo-oxygenase (COX)-2 and the inability of IL-18 to cause fever (Lee et al., 2004).
The activation of IL-18 by ICE led to the conclusion that this cytokine is related to IL-1β, which is also activated by ICE. Gingival and dermal fibroblasts have been reported to produce ICE and IL-1β, but not IL-18, not even after stimulation with P. gingivalis or E. coli LPS (Tardif et al., 2004). This suggests that ICE, for which IL-1β and IL-18 are specific substrates, is used by the gingival fibroblast solely for IL-1β production (Tardif et al., 2004). In contrast, caspase-3 (CPP32) cleaves both the precursor and the mature forms of IL-18, generating inactive degraded products. Therefore, CPP32 may constitute a potential down-regulator of IL-18 (Akita et al., 1997), and may represent a mechanism by which to regulate IL-18 activity.
The inflammasome (also called NALP1, NALP2/3) is a multiprotein complex of more than 700 kDa that acts as a molecular platform for the activation of the pro-inflammatory caspases 1 and 5 by the TLRs during the cell’s response to microbial challenge, leading to the processing and secretion of IL-1β and IL-18 (Martinon et al., 2002; Tschopp et al., 2003; Petrilli et al., 2005). An example of this is that gout-associated uric acid crystals engage the inflammasome (caspase-1-activating NALP3), resulting in the production of active IL1β and IL-18 (Martinon et al., 2006). NALP1 is widely expressed in the heart, kidney, and liver, with the highest expression levels found in peripheral blood cells, the thymus and spleen (Chu et al., 2001). But little is known about the natural stimuli that lead to the assembly and activation of the inflammasome.
IL-18 is produced mainly by antigen-presenting cells (APCs) (Biet et al., 2002), and also by non-immune cells, such as intestinal and airway epithelial cells, osteoblastic stromal cells (Nakanishi et al., 2001b), chondrocytes, adrenal cortex cells (Kashiwamura et al., 2002), and oral epithelial cells (Sugawara et al., 2001; Rouabhia et al., 2002). Its generation is subject to several regulatory mechanisms at the transcriptional, translational, and post-translational levels (Nakanishi et al., 2001b).
IL-18 synergizes with IL-12 to induce IFN- production from natural killer (NK) and T-cells and, therefore, Th1 cell development, but does not depend on IL-12 for its activity (Okamura et al., 1995; Nakanishi et al., 2001b; Biet et al., 2002; Lotze et al., 2002). In the absence of IL-12, IL-18 has been shown to induce the production of IL-4, IL-5, IL-10, and IL-13 by T- and NK cells, and also prostaglandin E2 (PGE2) production by activated macrophages (Kashiwamura et al., 2002). IFN- is essential for activating macrophage microbicidal activity, as well as promoting subsequent Th1-like immunity. While IL-12 and IL-18 play a major role in IFN- induction, it has also been shown that PGE2 has the capability to antagonize the potent inductive signal provided by the combination of IL-12 and IL-18 (Walker and Rotondo, 2004). It has been demonstrated that physiological concentrations of PGE2 significantly suppressed NK cell IFN- synthesis, regardless of cytokine stimulation. PGE2 may thus play an important role in limiting the innate and adaptive immune processes through direct suppression of NK cell IFN- synthesis (Walker and Rotondo, 2004).
As stated above, IL-18, in the absence of IL-12, induces the production of Th2 cytokines from T-cells, NK cells, and also basophils/mast cells (Nakanishi et al., 2001b). However, large amounts of IFN-, as well as IL-12Rβ2 expression on T-cells, are induced in response to IL-12 and IL-18 (Chang et al., 2000). Therefore, IL-18 stimulates either Th1 or Th2 responses, depending on its local cytokine milieu. Additionally, in the presence of IL-2, IL-18 induces naïve T-cells to produce IL-4 and IL-13, i.e., a Th2 profile. Stimulation with antigen not only increases IL-4 production, but also induces the T-cells to develop a Th2 profile (Nakanishi et al., 2001b; Delaleu and Bickel, 2004). Furthermore, either alone or in combination with IL-4, IL-18 is known to induce murine Th2 differentiation (Yoshimoto et al., 2000). IL-18 therefore enhances IL-12 and IL-2 activities and also those of IL-10, and markedly enhances IFN-, IL-1β, granulocyte-macrophage colony-stimulating factor (GM-CSF), and TNF production, making it, like IL-12, a remarkable pro-inflammatory cytokine (Lotze et al., 2002). Hence, it is evident that IL-18 has the capability to stimulate innate immunity as well as both Th1 and Th2 immune responses (Dinarello, 1999; Nakanishi et al., 2001b; Biet et al., 2002; Kawakami, 2002; Lotze et al., 2002), and is not a specific inducer of Th1 response, as has been suggested (Jonak et al., 2002). A comparison of the biological activities of IL-18 and IL-1β is shown in the Table (modified from Dinarello, 1999, and Biet et al., 2002).
Fig. 2 summarizes the role of IL-18 in adaptive and innate immune responses.
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Figure 2. IL-18 roles in adaptive and innate immunity. IL-18 is produced by several cells from the innate and adaptive immune systems, on stimulation by LPS, FasL, or interferons. The target cells of IL-18 include innate as well as adaptive immune cells. IL-18 exerts a synergistic effect with IL-12. IL-18 signals through a heterodimeric receptor, which recruits MyD88 and leads to the activation of the NF-B and AP-1 transcription factors (left inset). IL-18 signaling drives (top inset) the transcription of a set of cytokines (IFN-, TNF, IL-4, IL-6, IL-8), growth factors (GM-CSF]), and enzymes (NOS, COX-2, MMP3). However, IFN- is considered to be the key molecule induced by IL-18. MØ, macrophages; DC, dendritic cells; NOS, NO synthase; COX2, cyclo-oxygenase 2; MMP3, stromelysin; TIR, Toll/IL-1R domain; IL-18BP, IL-18-binding protein; IRAK, IL-1 receptor–associated kinase; TRAF6, TNF receptor–associated factor 6; IL-18R,β, and β chains of IL-18 receptor. Adapted and modified from Caligiuri et al.(2005).
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Nevertheless, IL-18 is chemotactic for CD4+ T-cells, primarily human Th1 cells that express high levels of IL-18R. CD4+, but not CD8+, T-cells have been shown to migrate in response to IL-18 into the synovia of persons with rheumatoid arthritis. This explains, in part, the contribution of acquired immune response development and the maintenance of chronic immunity in diseases such as rheumatoid arthritis (Komai-Koma et al., 2003). Another study has reported that chemotaxis of human NK cells is enhanced by IL-18, which also induces the production of activated MMP-2 and pro-MMP-2, as well as MT1-MMP, from these cells (Ishida et al., 2004b).
IL-18 is involved in the maturation of myeloid dendritic cells into mature dendritic cells (DCs), since it increases related genes, proteins, and activities; however, it has little effect on monocytes or the differentiation of monocytes to DCs, which means that IL-18 is involved in the activation of the adaptive immune response, specifically via the activation of the myeloid compartment (Li et al., 2004).
In addition to the above, IL-18 plays an important role in the activation of non-T-cell populations, such as macrophages, neutrophils, endothelial cells, synovial fibroblasts, chondrocytes, osteoclasts, and keratinocytes (Leung et al., 2001; Nakanishi et al., 2001b; Liew et al., 2003; Ishida et al., 2004a). It promotes Fas-dependent apoptosis of endothelial cells, hepatocytes, and basophils (Chandrasekar et al., 2004; Finotto et al., 2004; Schneider et al., 2004).
IL-18 has also been implicated in skin diseases such as eczema and psoriasis. It has been demonstrated that there is a significantly higher expression of IL-18R in keratinocytes of persons with psoriasis as compared with normal individuals. The keratinocytes responded to IL-18 with an up-regulation of the major histocompatibility complex (MHC) class I and II expression, and production of the chemokine CXCL10, suggesting that IL-18 may also contribute to the chronicity of inflammatory skin diseases (Wittmann et al., 2005).
IL-18 may well play a role in atherogenesis by up-regulation of the CXCL16 scavenger receptor on macrophages and smooth-muscle cells, leading to enhanced foam cell production and fatty streak growth (Tenger et al., 2005). High serum levels of IL-18 have been found in persons with congestive heart failure, showing a positive correlation between IL-18 levels and disease severity (Seta et al., 2000a,b).
Elevated plasma IL-18 concentrations have been associated with poor clinical outcome in severe inflammatory and septic conditions. This is how IL-18 has been proposed as a marker in monitoring severe inflammatory conditions and, in particular, suspected Gram-positive sepsis (Tschoeke et al., 2006). Likewise, IL-18 levels have been used as an early predictive biomarker of acute kidney injury after cardiopulmonary bypass surgery (CPB). IL-18 increases 4-6 hours after CPB, peaks at 12 hours, and remains elevated for the next 24-48 hours, whereas creatinine levels do not accurately reflect kidney function until several days after the procedure (Parikh et al., 2006).
Overall, therefore, it can be seen that IL-18 is central to many inflammatory diseases, including autoimmunity, inflammatory arthritis, atherosclerosis, and possibly periodontal disease.
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IL-18 AND PERIODONTAL DISEASE
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It is largely accepted that the control of Th1/Th2 balance is central to the immunoregulation of periodontal disease (Seymour and Gemmell, 2001; Gemmell and Seymour, 2004; Seymour and Taylor, 2004). It is also manifest that IL-18 stimulates both Th1- and Th2-mediated responses, depending on the presence or absence of IL-12 (Dinarello, 1999; Nakanishi et al., 2001a,b; Biet et al., 2002; Kawakami, 2002; Lotze et al., 2002). In this context, the study of IL-18 in periodontal disease would be of interest.
In addition to its capacity to act as a potent co-stimulus for Th1 induction, and its ability to induce TNF- and IL-1β in mononuclear cells, IL-18 is able to initiate a cytokine cascade with a concomitant increased expression of pro-inflammatory markers, such as chemokines, nitric oxide, adhesion molecules, and MMP-9 (Kohka et al., 1998; Nold et al., 2003). These events also occur in chronic periodontal inflammation. Based on in situ hybridization studies of tissue extracts and gingival crevicular fluid, Page et al. suggested that periodontal health is characterized by low levels of pro-inflammatory cytokines (IL-1β, TNF-, IFN-), PGE2, and MMPs, and by high levels of tissue inhibitors of metalloproteinases and cytokines that suppress the immuno-inflammatory response (IL-10, TGF-β, IL-10ra) (Page et al., 1997).
There have been several reports relating the up-regulation of IL-18 to human inflammatory and autoimmune diseases, including rheumatoid arthritis (Yamamura et al., 2001), psoriasis (Koizumi et al., 2001), type I diabetes (Nicoletti et al., 2001), atherosclerosis (Mallat et al., 2001), and chronic heart failure/coronary heart disease (Blankenberg et al., 2003; Yndestad et al., 2003). In some of these diseases, IL-18 clearly correlated with clinical severity (Muhl and Pfeilschifter, 2004). Interestingly, periodontal disease has also been associated as a risk factor for some of these diseases (DeStefano et al., 1993; Beck et al., 2001; Beck and Offenbacher, 2001). However, as yet, there is little information concerning the role of IL-18 in the initiation and progression of periodontal disease. Johnson and Serio (2005) have recently reported on the concentrations of IL-2, IL-4, IL-6, IL-10, IL-12, IL-18, and IFN- in the gingival tissues of Dominican Republic Hispanic individuals with healthy and diseased periodontium. Diseased periodontal tissues displaying bleeding on probing were subdivided into 3, 4 to 6, and > 6 mm probing depths. Concentrations of all the cytokines adjacent to 4-6-mm diseased sites were greater than in healthy sites, where IL-12 concentrations were higher. IL-6 and IL-18 concentrations were greater adjacent to > 6 mm sites compared with healthy sites. IL-6 and IL-18 were positively correlated with deep probing depths, while IFN- and IL-12 demonstrated negative correlations. It was suggested that IL-18 and IL-6 accumulate within the gingiva, possibly contributing to a non-resolving hyper-inflammation mediated by a shift toward a Th2 phenotype (Johnson and Serio, 2005).
As stated above, IL-18 is up-regulated during rheumatoid arthritis (Yamamura et al., 2001). Periodontitis and rheumatoid arthritis are chronic inflammatory disorders that share similar biological mechanisms of tissue destruction. Persons with rheumatoid arthritis display a poorer periodontal status (Mercado et al., 2001), and an incipient attachment loss has been reported more frequently in those with juvenile idiopathic arthritis (JIA) than in control individuals, despite having similar amounts of plaque and marginal bleeding (Miranda et al., 2003). This study examined neutrophil activity and pro-inflammatory cytokines in the two groups, and found significantly elevated serum levels of IL-1β and IL-18 in the JIA group. When the JIA group was subdivided according to the presence or absence of attachment loss, IL-18 was significantly increased in the subgroup with attachment loss. There were no differences in elastase activity and IL-1β concentrations in the gingival fluid between the groups, although IL-18 was not measured in the gingival fluid. It was suggested that the increased frequency of incipient attachment loss observed in these individuals might be due to their altered systemic inflammatory responses, with increased levels of serum IL-18 and IL-1β making them more prone to periodontal disease progression. Also, these more "inflamed" individuals could respond more destructively to the bacterial challenge in the periodontal environment (Miranda et al., 2005).
More recently, the local cytokine response has been evaluated in relation to clinical periodontal status, by determination of the concentrations of IL-1β, IL-12p40, IL-12p70, and IL-18 in the gingival crevicular fluid (GCF) obtained from gingivitis and periodontitis sites, as well as in the serum of persons with gingivitis and periodontitis. It was found that IL-1β and IL-18 concentrations were higher in the GCF from persons with periodontitis than in those with gingivitis, with IL-18 concentrations being higher than those of IL-1β. Very little IL-12, either p40 or p70, was detected in the gingival fluid samples. Very low levels of cytokines were found in serum. The level of serum IL-12 p40, however, was higher compared with the levels found in the gingival fluid from periodontitis sites in persons with periodontitis. The local production of IL-1β and IL-18 in the gingival crevicular fluid increased with increasing inflammation, and IL-18 was the predominant cytokine at both gingivitis and periodontitis sites. Very little IL-12 was detected, with levels decreasing with increasing inflammation. Therefore, it was suggested that there is an association between the severity of periodontal disease and IL-1, IL-12, and IL-18 levels (Orozco et al., 2006).
As already stated, epithelial cells express IL-18 as either a 24-kDa pro-IL-18 or as the active form at the site of inflammation. With the participation of serine proteases (stored in azurophil granules of PMNs), LPS, and IFN- priming via a caspase-1 independent pathway, the proactive form becomes activated. Therefore, it is likely that IL-18 is secreted by oral epithelial cells in the course of inflammation induced by LPS-producing pathogens via a direct or indirect response to those pathogenic organisms, and after infiltration by active PMNs into the inflamed site (Sugawara et al., 2001).
The effects of biomaterials on the expression of IL-18 have also been studied. Hydroxyapatite (HA), which is used to coat some dental implants, may activate phagocytic cells, to induce a cascade reaction leading to bone resorption. The phagocytosis of the smallest and needle-shaped HA particles by human monocytes leads to the release of TNF- and IL-6, cytokines involved in osteoclast activation (Laquerriere et al., 2003). Grandjean-Laquerriere et al.(2004) investigated the ability of HA particles to induce production of active IL-18 by human monocytes. They used 10 HA-based powders that differed in size range, shape, and surface area, and demonstrated that HA particles can trigger IL-18 production in human monocytes. The parameter that demonstrated the greatest influence on the cells proved to be shape. The most significant production of IL-18 was observed when cells were exposed to needle-shaped particles (Grandjean-Laquerriere et al., 2004).
Periodontal disease is characterized by the loss of connective tissue attachment, together with the loss of alveolar bone (Page and Schroeder, 1976). Yamada et al.(2002) investigated the in vitro effect of IL-18 on osteoclastic bone-resorbing activity, and found that when different concentrations of IL-18 were applied to osteoclast-enriched cell cultures, bone-resorbing activity decreased. However, IL-18 together with IL-12, in much lower concentrations, had an increased effect on reducing bone-resorbing activity, whereas IL-12 alone had no significant effect. This synergistic effect could be due to the fact that IL-12 increases the responsiveness to IL-18 via an increase in IL-18 receptor expression (Xu et al., 1998). Also, the combination of the two cytokines synergistically increased the concentrations of IFN-, suggesting the importance of IFN- in the inhibition of osteoclastic bone-resorbing activity (Yamada et al., 2002).
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GENETIC POLYMORPHISMS
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Genetic factors contribute significantly to periodontal disease expression (Michalowicz, 1994a,b). It has been suggested that the genetic variance is attributed, in part, to allelic variations in the IL-1 gene cluster, which results in increased production of IL-1β and IL-1 (Kornman et al., 1997). Several studies have explored different genetic polymorphisms in an attempt to associate them with severity and/or susceptibility to periodontal disease (Lang et al., 2000; Cullinan et al., 2001; Fraser et al., 2003; Loos et al., 2003). Correlations of six IL-18 gene polymorphisms have been tested in relation to pre-disposition to periodontal disease. One hundred and 23 persons with periodontitis and 121 healthy control individuals were tested; however, no associations between the disease and the IL-18 polymorphisms were found (Folwaczny et al., 2005). Therefore, while several genetic polymorphisms—including IL-1, FcRIIa, and FcRIIIa—have been partially associated with susceptibility to periodontal disease, this appears not to be the case for IL-18 polymorphisms.
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IL-18 AND VIRUSES: IS THERE ANY LINK WITH PERIODONTAL DISEASE?
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The central role of IL-18 in the development of protective immunity against bacterial infections is well-established. Inhibition of IL-18 production with the use of anti-IL-18 antibodies has been demonstrated to lead to uncontrolled bacterial infections (Bohn et al., 1998). IL-18 also has protective properties against several viruses (Fujioka et al., 1999). Virus infection may up-regulate caspase-1 gene expression. Processing of pro-IL-18 by caspase-1 into biologically active mature IL-18 establishes a link in the regulation of IL-18 and IFN- production by macrophages, T-cells, and NK cells in response to viruses (Pirhonen, 2001). It has been demonstrated that the Epstein-Barr virus nuclear antigen (EBNA2) can induce the expression of the IL-18 receptor (IL-18R), both in Burkitt lymphoma and in non-transformed B-cell lines, allowing the infected cells to respond to IL-18. EBNA2 expression has also been associated with IL-18R expression in vivo in EBV-positive B-lymphomas from persons with AIDS (Pages et al., 2005). Recent studies have identified herpes viruses in periodontal disease, with EBV-1, human cytomegalovirus (HCMV), and other herpes viruses being present more frequently in periodontal lesions than in gingivitis or periodontally healthy sites (Contreras et al., 1999a). HCMV in periodontal lesions tends to be associated with the progression of periodontal disease, and it has been hypothesized that the virus infection may impede the normal defenses, allowing for the overgrowth of periodontal pathogens (Contreras et al., 1999a,b, 2000; Contreras and Slots, 2000; Slots and Contreras, 2000; Kamma et al., 2001). Given the effect of EBV on B-cells, the study of a relationship between IL-18 production in the gingival tissues and herpes viruses in diseased and healthy periodontium may be of interest.
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CONCLUSIONS
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Since its discovery by Okamura, IL-18 has been the subject of numerous studies aiming to understand its biological effects in the homeostasis of the immune system. IL-12 up-regulates the expression of the functional IL-18 receptor, and synergizes with IL-18 to enhance IFN- and IL-1β production. IL-18 has the capability of promoting the development of either a Th1 or a Th2 response in the presence or absence of IL-12, giving it a pivotal role in regulating innate and adaptive immunity in the development or control of periodontal inflammation.
While much is known about the production, signaling pathways, receptors, and biological effects of IL-18, further experimental studies are needed to understand the role of IL-18 in periodontal health and disease. This is particularly true when one considers the juxtacrine-controlled nature of tissue breakdown in the cytokine network.
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ACKNOWLEDGMENTS
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This work was supported by grant No. 10/2005 from the Australian Dental Research Foundation Inc. MB is supported by a grant from the Swiss Society of Odontology (SSO) Nr 222.
Received for publication February 23, 2006.
Accepted for publication September 23, 2006.
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Journal of Dental Research, Vol. 86, No. 7,
586-593 (2007)
DOI: 10.1177/154405910708600702
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ABSTRACT
INTRODUCTION