The expanding family of interleukin-1 cytokines and their role in destructive inflammatory disorders

Abstract

Understanding cytokine immunobiology is central to the development of rational therapies for destructive inflammatory diseases such as rheumatoid arthritis (RA) and periodontitis. The classical interleukin-1 (IL-1) family cytokines, IL-1α and IL-1β, as well as IL-18, play key roles in inflammation. Recently, other members of the IL-1 family have been identified. These include six cytokines whose genes are located downstream of the genes for IL-1α and IL-1β on chromosome 2 (IL-1F5-10) and also IL-33, which is the ligand for ST2, a member of the IL-1R/Toll-like receptor (TLR) receptor superfamily. IL-1F6, IL-1F8 and Il−1F9 are agonists and, along with their receptor IL-1Rrp2, are highly expressed in epithelial cells suggesting a role in immune defence in the skin and the gastrointestinal (GI) tract including the mouth. Synovial fibroblasts and articular chondrocytes also express IL-1Rrp2 and respond to IL-1F8, indicating a possible role in RA. IL-33 is associated with endothelial cells in the inflamed tissues of patients with RA and Crohn's disease, where it is a nuclear factor which regulates transcription. IL-33 is also an extracellular cytokine: it induces the expression of T helper 2 (Th2) cytokines in vitro and in vivo as well as histopathological changes in the lungs and GI tract of mice. Therapeutic agents which modify IL-1 cytokines (e.g. recombinant IL-1Ra) have been used clinically and others are at various stages of development (e.g. anti-IL-18 antibodies). This review highlights the emerging data on these novel IL-1 cytokines and assesses their possible role in the pathogenesis and therapy of destructive inflammatory disorders such as RA and periodontitis.

Introduction

Interleukin (IL)-1 cytokines (IL-1α, IL-1β and IL-1Ra) play an important role in immune regulation and inflammatory processes by inducing expression of many effector proteins, e.g. cytokines/chemokines, nitric oxide synthetase and matrix metalloproteinases (MMPs) [1]. Excessive and/or dysregulated activity of these mediators is associated with tissue destruction and therefore the synthesis, secretion and biological activity of IL-1 cytokines have been identified as therapeutic targets for common inflammatory disorders such as rheumatoid arthritis (RA) and periodontitis [2,3]. It is well established that blockade of tumour necrosis factor (TNF)-α has significant efficacy in the treatment of RA and although IL-1 (and IL-6) inhibition has not yet achieved widespread clinical application, there are some examples of inflammatory disorders in which IL-1 blockade may confer additional benefits [4–6].

IL-18 is important in both innate and acquired immune responses; it stimulates neutrophil migration and activation as well as T helper 1 (Th1) cell differentiation and interferon (IFN)-γ secretion in a variety of cell types. IL-18 has a role in destructive inflammatory disorders [7] and is a potential therapeutic target although, currently, anti-IL-18 therapies are only at the preclinical trial stage [8]. It is recognized that existing ‘biopharmaceuticals’ such as those directed at IL-1 activity have limitations and that there is a need for novel therapeutics [9]. A better understanding of cytokine responses in human disease will be an important step towards that goal.

Recently, six novel members of the IL-1 cytokine family were identified by different research groups on the basis of sequence homology, three-dimensional structure, gene location and receptor binding [10–15]. Different names were assigned to these cytokines by the different groups, but the nomenclature for the IL-1 family was subsequently revised and a systematic scheme proposed [11]. Thus, IL-1α, IL-1β, IL-1Ra and IL-18 became IL-1F1, IL-1F2, IL-1F3 and IL-1F4, respectively (Table 1). However, IL-1α/α, IL-1Ra and IL-18 are the names which are used most commonly in the literature and, as they are immediately recognizable, will continue to be used in this review. In accordance with the new nomenclature, the novel IL-1 family cytokines are referred to as IL-1F5-10. More recently, IL-33 (IL-1F11) has been identified as another IL-1 cytokine on the basis of its structural and functional similarities to other IL-1 family members [16]. Understanding the immunobiology of these IL-1 cytokines promises to provide further insight into the pathogenesis of immune-inflammatory diseases and may help to identify novel therapeutic targets.

Table 1.

Interleukin (IL)-1 cytokine family: nomenclature and function.

Cytokine	Other names	Systematic name	Immunological function
IL-1α	IL-1 and leucocyte activating factor (LAF) (both collectively with IL-1β)	IL-1F1	IL-1R1 agonist with proinflammatory action but mainly acts as an intracellular transcriptional regulator
IL-1β	IL-1 and leucocyte activating factor (LAF) (both collectively with IL-1α)	IL-1F2	Acts synergistically with TNF-α, activates proinflammatory responses in a wide range of cells, increases expression of adhesion molecules in endothelial cells and promotes diapedesis and the acute phase response
IL-1Ra		IL-1F3	IL-1RI antagonist, prevents IL-1-dependent signalling
IL-18	IFN-γ inducing factor (IGIF), IL-1γ	IL-1F4	Induces IFN-γ production from T lymphocytes and NK cells and acts synergistically with IL-12 to promote the Th1 response
IL-1F5	IL-1Hy1, FIL1δ, IL-1L1, IL-1δ, IL-1H3, IL-1RP3	IL-1F5	Possible IL-1Rrp2 receptor antagonist
IL-1F6	FIL1ε	IL-1F6	Agonist via the IL-1Rrp2 receptor. Increases IL-6, IL-8 production in epithelial cells
IL-1F7	FIL1ζ, IL-1H4, IL-1RP1, IL-1H1	IL-1F7	Interacts with IL-18 binding protein to reduce IL-18 activity
IL-1F8	FIL-1η, IL-1H2	IL-1F8	Agonist via the IL-1Rrp2 receptor. Increases IL-6, IL-8 production in epithelial cells. Also up-regulates IL-6 and IL-8 production in chondrocytes and synovial fibroblasts
IL-1F9	IL-1H1, IL-1RP2, IL-1ε	IL-1F9	Agonist via the IL-1Rrp2 receptor. Increases IL-6, IL-8 production in epithelial cells
IL-1F10	IL-1Hy2, FKSG75	IL-1F10	Binds soluble IL-1RI, function unknown
IL-33	NF-HEV	IL-1F11	ST2 receptor agonist. Induces Th2 cytokine expression. Intracellular transcriptional regulator in endothelial cells

IFN: interferon; NK: natural killer; Th: T helper; TNF: tumour necrosis factor.

IL-1 family synthesis, processing and secretion

A variety of proinflammatory mediators induce IL-1 cytokine transcription; these include pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS), and proinflammatory cytokines such as TNF-α, IFN-α and IFN-β and IL-1β itself. The receptors for IL-1 cytokines are structurally related to pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs), which recognize LPS and other PAMPs [17]. The intracellular signalling molecules which mediate the proinflammatory action of PAMPs are identical to those involved in IL-1 signalling via the type I IL-1 receptor (IL-1RI) [18]. Activation of IL-1RI leads to recruitment of adaptor molecules such as MyD88 and activation of IL-1R-associated kinases (IRAK), leading to activation of nuclear factor (NF)-κB and mitogen-activated protein kinase (MAPK)-regulated transcription factors such as c-jun n-terminal kinase (JNK) and p38 [19]. NF-κB is particularly important in transcriptional regulation of the IL1B gene (and the IL18 gene) in response to PAMPs, but other transcription factors such as Spi-1 (PU.1) also have important roles [20]. Little is known about regulation of expression of IL-1F5-10, although IL-1F6, 8 and 9 are all up-regulated in response to LPS in monocytes, presumably via similar signalling pathways to those that regulate IL-1β responses [15]. TNF-α and IL-1β are activators of IL-33 transcription in fibroblasts and keratinocytes, but LPS induces only a very modest up-regulation of IL-33 mRNA in dendritic cells and macrophages [16].

RNA stability and translational control also contribute to IL-1 regulation. The p38 MAPK pathway stabilizes inflammatory response protein mRNAs [21,22] and promotes their translation [23]. This occurs via a mechanism involving AU-rich elements (AREs) in the 3′ untranslated region (UTR) of the mRNA. For example, a downstream protein kinase MK2 is thought to modulate the activity of the ARE-binding and mRNA-destabilizing protein tristetraprolin (TTP) [24]. IL-18 mRNA lacks the destabilization sequence in the 3′UTR, which may explain the constitutive expression of IL-18 in peripheral blood mononuclear cells (PBMC) and non-immune cells [25]. Whether this type of regulation occurs with IL-1F5-10 and IL-33 is not clear. Although IL-1F8 was detected in serum from healthy donors, it was not found to be up-regulated significantly in serum from patients with RA or septic shock, which suggests that IL-1F8 may be expressed constitutively [26].

IL-1α and IL-1β are translated as 31 kDa leaderless pro-cytokines. IL-1α is already active in this form, whereas IL-1β is cleaved intracellularly by caspase-1 (also known as IL-1β converting enzyme) to the 17 kDa active form [27]. IL-18 also lacks a signal peptide and is processed by caspase-1 from a 24-kDa precursor to the active 18 kDa peptide [27]. Recently IL-33 has been shown to be processed in a similar manner by caspase-1 in vitro, but a more recent study failed to find any evidence for caspase-1 processing of IL-33 in vivo[16,28]. IL-1F5, -6, -8, -9 and -10 lack signal pro-peptides and, to date, no caspase-1 cleavage sites have been identified [29–31]. However, IL-1F7 contains a putative signal pro-peptide and has been shown to be cleaved by caspase-1 [32].

It has been postulated that cells such as monocytes require a second stimulus to release active IL-1 cytokines. The initial stimulus, e.g. LPS, causes large accumulation of pro-IL-1β in the cytosol and only a modest IL-1β secretion [27]. IL-1β release is induced strongly by extracellular adenosine triphosphate (ATP), which signals via the P2X₇R receptor causing K⁺ efflux from cells activating procaspase-1 and hence pro-IL-1β processing [33]. Secretion of IL-18 involves a similar mechanism [34]. There is evidence to suggest that that IL-1β may be packaged into small plasma membrane microvesicles that are released into the extracellular space [35] or into endocytotic vesicles [36]. Details of the intracellular processing and secretion of the remaining IL-1 family cytokines remain to be determined.

Functional effects of IL-1 family cytokines

Both IL-1α/β mediate their activity via IL-1RI [37]. Upon ligand binding to IL-1RI, IL-1R accessory protein (IL-1RAcP or AcP) is recruited to the complex and is involved in signal transduction [38]. The IL-18 receptor (IL-18R) complex is homologous to the IL-1RI complex and requires IL-18R accessory protein (AP) signalling [38]. IL-1F6, 8 and 9 all act via the IL-1/TLR family receptor IL-1Rrp2 (and not IL-1RI), and activate both NF-κB and MAPK pathways leading to up-regulation of IL-6 and IL-8 in responsive cells [12,15]. Recruitment of IL-1RAcP is also required for signalling via IL-1Rrp2 [15]. A consistent finding has been that the novel IL-1 family members are only biologically active at concentrations some 100–1000-fold greater than those observed for IL-1β, although this may be an artefact of the model systems used [12,15]. The extracellular form of IL-33 stimulates target cells by binding to the IL-1R/TLR superfamily member ST2 and subsequently activates NF-κB and MAPK pathways via identical signalling events to those observed for IL-1β[16]. However, IL-33 is also associated with heterochromatin in the nuclei of endothelial cells, where it functions as a transcriptional repressor [28]. Thus IL-33 may be a dual function cytokine with both extracellular and intracellular functions, a property it shares with IL-1α. The precise biological role of IL-33, and in particular that of its intracellular form, remain to be determined.

Similar to IL-1α and IL-β, IL-18 is secreted by a variety of cell types including monocytes, macrophages, dendritic cells, epithelial cells, keratinocytes and synovial fibroblasts and is important in inflammation and host response to infection [7,34,39]. IL-18 plays a role in both innate and adaptive immunity by activating neutrophils and enhancing T and NK cell maturation [7].

New data are now emerging regarding the immuno-pathological roles of IL-33 and IL-1F6, 8 and 9. IL-1F6, 8 and 9 are expressed predominantly in the skin [15]. Furthermore, IL-1F6 is also expressed in the trachea and thymus, IL-1F8 in skeletal muscle and glial cells [40], and IL-1F9 in the trachea, uterus and in bronchial epithelia [41]. The receptor for these cytokines, IL-1Rrp2, is also most highly expressed in skin and in mammary and mucosal epithelial cell lines [12,15]. It is interesting that although haematopoietic cells are the main source of IL-1β and IL-18 they are not the predominant source of IL-33 and IL-1F5-10 [12,15]. In humans, IL-33 was found to be expressed constitutively in smooth muscle and in bronchial epithelia, while expression can be induced by IL-1β and TNF-α in lung and dermal fibroblasts [16]. The IL-33 receptor ST2, in its transmembrane form, is expressed primarily on Th2 and mast cells and has been shown previously to be required for the development of effective Th2 responses [42]. Administration of purified IL-33 in vitro and in vivo induces Th2-associated cytokines, IL-5, IL-13 and reduced production of IFN-γ from Th1 cells [16]. Furthermore, when IL-33 is administered intraperitoneally to mice, this increases the number of splenic eosinophils, mononuclear cells and plasma cells but not neutrophils. In the lungs vascular changes were evident, such as moderate medial hypertrophy and the presence of infiltrates of eosinophils and mononuclear cells beneath the endothelium [16]. In light of these pathological changes, IL-33 may play a role in diseases such as asthma, other inflammatory airway diseases and inflammatory bowel disease [43]. IL-33 is associated with endothelial cells within human tonsils, the rheumatoid synovium and intestinal tissue from patients with Crohn's disease [28].

Regulation of the biological activity of IL-1 cytokines

Signalling via the IL-1RI receptor can be blocked by the binding of the receptor antagonist, IL-1Ra. In addition, a second receptor, IL-1RII, binds IL-1α/β as a decoy receptor and does not recruit the necessary proteins for signal transduction [44]. IL-18 activity is down-regulated through interaction with IL-18 binding protein (IL-18bp) which binds and sequesters IL-18 [45].

IL-1F6, 8 and 9 are agonists, but there are no known regulators of their biological activity. Although IL-1F5 and IL-1F10 share some amino acid sequence homology with IL-1Ra [13,14], it is not yet clear whether they also share its antagonist properties: IL-1F5 was shown to inhibit NF-κB activation by IL-1F9 mediated through IL-Rrp2, but this finding has not been reproduced [12,15]. The IL-33 receptor ST2 is alternatively spliced to produce a secreted soluble form and a transmembrane form [46]. Secreted ST2 can bind to the surface of B cells and myeloma cells [47] and furthermore was shown to suppress IL-6 production in human THP-1 monocytes following LPS stimulation [48]. At present, the mechanism of ST2 suppression of proinflammatory cytokine production is unclear, although it has been shown to involve ST2 binding to monocytic plasma membranes and subsequent inhibition of NF-κB activation [48]. Secreted ST2 may exert its immunosuppressive action via interaction with its ligand IL-33 although there are, as yet, no data to support this conjecture [16,43].

IL-1 family cytokines in RA and periodontitis

Inflammation is clearly a central component of many chronic diseases. Furthermore, it is increasingly clear that RA and periodontitis share immunopathogenic mechanisms and that there is a cross-susceptibility between these diseases [49,50]. In addition, the success of anti-cytokine therapies for RA has meant that this disease serves as a paradigm for the development of similar approaches for other chronic inflammatory disorders [6].

RA is characterized by inflammation of the synovial membranes and cartilage and bone resorption [51]. The most prevalent form of periodontitis is chronic periodontitis, which is an inflammatory disease initiated by pathogenic bacteria in the subgingival plaque biofilm [52]. Periodontitis is characterized by loss of connective tissues within the periodontium and destruction of (alveolar) bone support. Although there are fundamental differences in the aetiology and anatomical involvement of periodontitis and RA, similar cell lineages are directly involved in the pathogenesis of both disorders. Fibroblasts and osteoclasts are key mediators of tissue destruction in both diseases, mainly via secretion of MMPs [53,54]. Furthermore, a prominent, localized inflammatory cell infiltrate involving neutrophils, monocytes and both T and B lymphocytes is another common characteristic [49]; these cells are further sources of MMPs and the cytokines that regulate them.

IL-1 cytokines are key mediators of immune responses, inflammation and tissue destruction in both RA and periodontitis. IL-1β levels are elevated in synovial fluids from RA patients [55] and IL-1β is produced by synovial tissue macrophages, activated T cells, fibroblasts and chondrocytes [56]. The local effects of IL-1β include increased leucocyte migration into the synovium and increased tissue turnover through the induction of MMP expression [57]. IL-1β is also prominent in periodontal tissue and gingival crevicular fluid of patients with periodontitis and is stimulated in a variety of resident and immune cells by components of oral bacteria (e.g. LPS) [58]. Excessive IL-1β in both disorders accounts for increased local blood flow, neutrophil infiltration and activation of connective tissue turnover via stimulation of MMP secretion from osteoclasts, fibroblasts and neutrophils [51,59].

IL-18 is present in the synovial membranes of patients with RA and psoriatic arthritis [7]. CD14⁺/CD68⁺ macrophages and synovial fibroblasts are the major sources of IL-18 within the inflamed joint [7]. IL-18R and IL-18 binding protein can also be detected in synovial fluid [7]. Synovial IL-18 levels correlate with RA disease activity and response to therapy. IL-18 is thought to amplify the inflammatory response by promoting the release of other cytokines, in particular TNF-α, granulocyte–macrophage colony-stimulating factor (GM-CSF) and IFN-γ. IL-18 has also been shown to promote angiogenesis, prevent endothelial cell and fibroblast apoptosis and modulate various cell lineages, including keratinocytes, osteoblasts, osteoclasts and chondrocytes, in RA [39,60]. Measurements of IL-18 in periodontal tissue and in the circulation indicate that IL-18 is associated with active periodontitis although there are, as yet, no direct functional data linking this cytokine with destructive processes in periodontitis [61,62].

Recently, IL-1F8 was shown to induce the production of inflammatory mediators by primary human synovial fibroblasts and articular chondrocytes, indicating a potential role for this cytokine in the pathogenesis of RA, and both these cell types express IL-1Rrp2 [26]. IL-1F8 stimulates transcription of IL-6 and IL-8 mRNA in fibroblasts and chondrocytes and nitric oxide production in chondrocytes. IL-1F8 levels in synovial fluid are similar to those in matched serum samples, indicating that the joint itself is not a major source of IL-1F8 [26].

IL-33, in its intracellular form, is highly expressed within endothelial cells in the RA synovium, suggesting a pathogenic role [28]. Also, one can speculate that synovial fibroblasts stimulated by IL-1β or TNF-α may be a source of extracellular IL-33 in the joint. However, RA is considered to be a Th1-driven disease [63] and IL-33 is a potent inducer of the Th2 response [16]; consequently IL-33 treatment may have a therapeutic benefit in RA but clinical trials with IL-10 (another Th2 cytokine) have not been successful [64]. In addition to promoting Th2 responses, IL-33 also induces mononuclear cell infiltration and epithelial hyperplasia in the mucosal tissues of mice [16], and synovial hyperplasia is a key feature of RA. Significantly, soluble ST2 receptor treatment has been shown to ameliorate pathological changes significantly in collagen-induced arthritis in mice by reducing levels of IL-6, IL-12 and TNF-α[65]. Therefore, these data show that IL-33-based therapy may prove efficacious for treating RA.

Although there are no direct data indicating a role for novel IL-1 cytokines in periodontitis, IL-1F6, 8 and 9 have similar agonist activities to IL-1β and activate MAP kinases and NF-κB leading to secretion of IL-6 and IL-8 [15]. It is also interesting to note that IL-1F6, 8 and 9 and their receptor IL-1Rrp2 have an expression pattern restricted largely to human skin keratinocytes and internal epithelial tissues which are exposed to pathogenic bacteria, such as in the trachea, lung and oesophagus [12,15]. In this context, keratinocytes of the gingival epithelium have been compared to epidermal keratinocytes inasmuch as they are immunocompetent cells, actively secreting cytokines in response to proinflammatory stimuli and are central to the pathogenesis of inflammatory disorders such as periodontitis [66,67]. Significantly, novel IL-1 cytokines and IL-1Rrp2 are up-regulated in keratinocytes in psoriatic skin lesions although there are, as yet, no data relating to the expression of novel IL-1 cytokines or their receptors in the periodontal tissues [12,15]. Increased microvasculature is a prominent histological finding in periodontitis, so it would be interesting to investigate expression of IL-33 associated with endothelial cells in this tissue.

In addition to roles in inflammation, novel IL-1 cytokines may also mediate acquired immunity. The nature of the T cell response is key in determining the effectiveness of adaptive immunity [68]. IL-12, IL-18 and IFN-γ have important roles in bridging innate and adaptive immune responses and engaging T cells and myeloid immune cells, such as macrophages and dendritic cells [68,69]. Also, in vivo experiments in murine systems suggest that IL-33 has a role in promoting Th2 responses (such as those associated with destructive periodontitis) and also that systemic administration promotes a variety of pathological effects associated with inflammatory responses including mononuclear and neutrophilic infiltration of mucosal tissues and epithelial cell hyperplasia [16]. IL-33 probably has an important role in immune responses at a number of levels, but there are no direct data on the effects of this cytokine on cells of the innate immune response, and limited information concerning the role of IL-33 in chronic inflammatory disorders. Interestingly, the IL-33 receptor ST2 exists in a soluble form (sST2) which is secreted by activated fibroblasts and macrophages in vitro and is induced in vivo in inflammatory pathologies [42]. sST2 may function in post-secretory regulation of IL-33 analogous to similar systems regulating IL-1α and IL-18, and may serve to suppress damaging inflammatory responses induced by IL-33 [43]. Dinarello also speculates that IL-33 may have a role in regulation of mast cell activity, as mast cell expression of ST2 is a ‘prominent finding’[43]. Significantly, mast cells have a pathogenic role in mouse models of RA [70]. Mast cells may be the source of Th2 cytokines, but although mast cells are predominant features of the peridontitis lesion evidence that they drive the Th2 response in periodontitis is lacking [71].

Targeting IL-1 family cytokines for therapeutic intervention

The successful treatment of RA with TNF-α and IL-1 blockade has established cytokine therapy as a feasible method for the treatment of chronic inflammatory conditions. In contrast to TNF-α, IL-1α/β are detected after the early stages of disease, justifying the use of anti-IL-1 therapies in all stages of disease progression [3]. Increased understanding of IL-1 cytokine diversity and action has revealed a number of potential therapeutic targets (Fig. 1). At present, non-glycosylated recombinant sIL-1Ra, known as Anakinra (Kineret, Amgen Inc., Thousand Oaks, CA, USA), has been used to treat RA and other rheumatic disorders, such as adult onset Still's disease and systemic onset juvenile idiopathic arthritis [3]. Recent clinical studies indicate that Anakinra is a safe and well-tolerated treatment suitable for long-term use in RA [72], although its anti-inflammatory effects are inferior to those of anti-TNF-α treatments, due possibly to its short half-life [73]. Anakinra has also been used to treat the genetic disorder neonatal onset multi-system inflammatory disease, which results in excessive production of IL-1β[74]. Anakinra may prove useful in the treatment of other inflammatory conditions; however, at present there is a lack of published clinical data on the use of Anakinra in diseases such as colitis and psoriasis [6].

Fig. 1.

Regulation of interleukin (IL)-1 family cytokine signalling. IL-1 family cytokines activate target cells via structurally similar receptors [IL-1R/Toll-like receptor (TLR) family] and common intracellular signalling events. Cytokine binding and activation of these receptors is modified by a number of endogenous regulators (e.g. IL-1RII, IL-1Ra, IL-18bp). Synthetic versions of these molecules and synthetic antibodies have been developed and have potential efficacy in inflammatory diseases (e.g. Anakinra). In addition, a number of compounds have been developed which modulate post-receptor events in IL-1R/TLR signalling (e.g. TIR mimetics, IKK/NEMO inhibitors, etc.); these compounds represent an alternative strategy to modulating proinflammatory pathways in human disease. Abbreviations: MyD88: myeloid differentiation protein 88; IRAK1/4: IL-1R activated kinase 1/4; TRAF6: tumour necrosis factor (TNF) receptor-associated factor 6; TAK1 transforming growth factor (TGF)-β associated kinase 1; NEMO: nuclear factor (NF)-κB essential modulator; IκB inhibitor of NF-κB; IKK1/2: I κB kinase1; MAPKK: mitogen-activated protein kinase kinase; JNK: c-jun n-terminal kinase (see text for other abbreviations).

Two other IL-1-based therapies which have advanced to the clinical trial stage are IL-1 trap [3] and caspase-1 inhibitors, Pralnacsan and VX-765 [75,76]. These therapies have shown some efficacy in the treatment of periodic fever syndromes and familial cold autoinflammatory syndrome, respectively [3,76]. However, these therapies showed no benefit in the treatment of RA [3]. Targeting IL-1/TLR signalling pathways is the subject of intense research, and a number of promising compounds have emerged which may modulate IL-1 signalling to therapeutic advantage (Fig. 1) [9,77].

Research into the use of anti-cytokine therapies in the treatment of periodontitis is at an early stage, although exogenous sIL-1RI and sTNF-RII applied to the gingival tissue of primates with experimental periodontitis resulted in inhibition of inflammatory cell infiltration, alveolar bone loss and connective tissue breakdown [78–80]. Local delivery of anti-cytokine therapies into the periodontal pocket to achieve a local therapeutic dose with minimum systemic exposure may prove to be an attractive method of administering such agents, although clearly much research would be required to determine the optimum mode of delivery, the delivery vehicle, tissue compatibility and tolerability, as well as considerations of safety and efficacy. A precedent has already been set, however, as evidenced by the large range of antibacterial therapies that have been incorporated successfully into local delivery systems for use in treating periodontal disease that have now become part of mainstream clinical practice [81].

The immunopathological role of IL-18 has been well documented and anti-IL-18 therapies are currently in the early clinical trial stage [8]. This cytokine represents an amplification signal for components of the innate and adaptive immune responses and, as such, anti-IL-18 therapy may prove to be a powerful anti-inflammatory treatment for a spectrum of disorders. The functions of the other novel IL-1 family cytokines are less well documented and further studies are needed to understand their role in inflammatory processes and disease progression.

Limitations in the use of anti-cytokine therapies include opportunistic infections, cost and patient-related factors such as disease stage. Functional redundancy of cytokines and target tissue receptor expression may also limit effectiveness. Furthermore, in complex diseases such as RA and periodontitis, inflammation is induced and maintained by networks of cytokines rather than just one mediator. An emerging principle is that patterns of cytokine expression may vary between individuals, and therefore patient genotype will influence immunoregulation and response to therapy [82]. Therefore, currently available anti-cytokine therapies are not always effective, and this has led to the investigation of other cytokine targets [8].

Conclusions

RA and periodontitis are examples of common diseases with a destructive inflammatory pathogenesis. Although the aetiological triggers for these diseases are distinct, they have a similar immunopathogenesis driven by proinflammatory cytokines. The IL-1 cytokines are important in both diseases, and understanding their synthesis and action has led to the development of novel therapeutic agents. Recently, seven further members of the IL-1 family (IL-1F5-10 and IL-33) have been identified. These molecules share many features associated with IL-1α, IL-1β and IL-18, but also exhibit some interesting differences in their biological activity and expression pattern. Although evidence for a role of these novel IL-1 cytokines in inflammatory diseases is limited and mostly indirect, there is sufficient information to suggest that understanding the immunobiology of these molecules might reveal novel therapeutic approaches for common and economically important diseases such as RA and periodontitis.