• 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. Aug 2007; 149(2): 217–225.
PMCID: PMC1941943

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.

Keywords: inflammation, interleukin-1, periodontitis, rheumatoid arthritis

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 [46].

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 [1015]. 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.

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 [2931]. 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 ...

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 [7880]. 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.

References

1. Dinarello CA. The IL-1 family and inflammatory diseases. Clin Exp Rheumatol. 2002;20:S1–13. [PubMed]
2. Salvi GE, Lang NP. Host response modulation in the management of periodontal diseases. J Clin Periodontol. 2005;32(Suppl. 6):108–29. [PubMed]
3. Burger D, Dayer JM, Palmer G, Gabay C. Is IL-1 a good therapeutic target in the treatment of arthritis? Best Pract Res Clin Rheumatol. 2006;20:879–96. [PubMed]
4. Braddock M, Quinn A. Targeting IL-1 in inflammatory disease: new opportunities for therapeutic intervention. Nat Rev Drug Discov. 2004;3:330–9. [PubMed]
5. Dinarello CA. The many worlds of reducing interleukin-1. Arthritis Rheum. 2005;52:1960–7. [PubMed]
6. Moller B, Villiger PM. Inhibition of IL-1, IL-6, and TNF-alpha in immune-mediated inflammatory diseases. Springer Semin Immunopathol. 2006;27:391–408. [PubMed]
7. Gracie JA, Robertson SE, McInnes IB. Interleukin-18. J Leukoc Biol. 2003;73:213–24. [PubMed]
8. Anderson EJ, McGrath MA, Thalhamer T, McInnes IB. Interleukin-12 to interleukin ‘infinity’: the rationale for future therapeutic cytokine targeting. Springer Semin Immunopathol. 2006;27:425–42. [PubMed]
9. O'Neill LA. Targeting signal transduction as a strategy to treat inflammatory diseases. Nat Rev Drug Discov. 2006;5:549–63. [PubMed]
10. Dunn E, Sims JE, Nicklin MJ, O'Neill LA. Annotating genes with potential roles in the immune system: six new members of the IL-1 family. Trends Immunol. 2001;22:533–6. [PubMed]
11. Sims JE, Nicklin MJ, Bazan JF, et al. A new nomenclature for IL-1-family genes. Trends Immunol. 2001;22:536–7. [PubMed]
12. Debets R, Timans JC, Homey B, et al. Two novel IL-1 family members, IL-1 delta and IL-1 epsilon, function as an antagonist and agonist of NF-kappa B activation through the orphan IL-1 receptor-related protein 2. J Immunol. 2001;167:1440–6. [PubMed]
13. Taylor SL, Renshaw BR, Garka KE, Smith DE, Sims JE. Genomic organization of the interleukin-1 locus. Genomics. 2002;79:726–33. [PubMed]
14. Nicklin MJ, Barton JL, Nguyen M, FitzGerald MG, Duff GW, Kornman K. A sequence-based map of the nine genes of the human interleukin-1 cluster. Genomics. 2002;79:718–25. [PubMed]
15. Towne JE, Garka KE, Renshaw BR, Virca GD, Sims JE. Interleukin (IL)-1F6, IL-1F8, and IL-1F9 signal through IL-1Rrp2 and IL-1RAcP to activate the pathway leading to NF-kappaB and MAPKs. J Biol Chem. 2004;279:13677–88. [PubMed]
16. Schmitz J, Owyang A, Oldham E, et al. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity. 2005;23:479–90. [PubMed]
17. O'Neill LA. The interleukin-1 receptor/Toll-like receptor superfamily: signal transduction during inflammation and host defense. Sci STKE. 2000;2000:RE1. [PubMed]
18. Akira S, Takeda K. Toll-like receptor signalling. Nat Rev. 2004;4:499–511. [PubMed]
19. Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006;124:783–801. [PubMed]
20. Waterman WR, Xu LL, Tetradis S, et al. Glucocorticoid inhibits the human pro-interleukin lbeta gene (ILIB) by decreasing DNA binding of transactivators to the signal-responsive enhancer. Mol Immunol. 2006;43:773–82. [PubMed]
21. Kracht M, Saklatvala J. Transcriptional and post-transcriptional control of gene expression in inflammation. Cytokine. 2002;20:91–106. [PubMed]
22. Clark AR, Dean JL, Saklatvala J. Post-transcriptional regulation of gene expression by mitogen-activated protein kinase p38. FEBS Lett. 2003;546:37–44. [PubMed]
23. Kumar A, Lnu S, Malya R, et al. Mechanical stretch activates nuclear factor-kappaB, activator protein-1, and mitogen-activated protein kinases in lung parenchyma: implications in asthma. FASEB J. 2003;17:1800–11. [PubMed]
24. Brook M, Tchen CR, Santalucia T, et al. Posttranslational regulation of tristetraprolin subcellular localization and protein stability by p38 mitogen-activated protein kinase and extracellular signal-regulated kinase pathways. Mol Cell Biol. 2006;26:2408–18. [PMC free article] [PubMed]
25. Puren AJ, Fantuzzi G, Dinarello CA. Gene expression, synthesis, and secretion of interleukin 18 and interleukin 1beta are differentially regulated in human blood mononuclear cells and mouse spleen cells. Proc Natl Acad Sci USA. 1999;96:2256–61. [PMC free article] [PubMed]
26. Magne D, Palmer G, Barton JL, et al. The new IL-1 family member IL-1F8 stimulates production of inflammatory mediators by synovial fibroblasts and articular chondrocytes. Arthritis Res Ther. 2006;8:R80. [PMC free article] [PubMed]
27. Dinarello CA. Interleukin-1 beta, interleukin-18, and the interleukin-1 beta converting enzyme. Ann NY Acad Sci. 1998;856:1–11. [PubMed]
28. Carriere V, Roussel L, Ortega N, et al. IL-33, the IL-1-like cytokine ligand for ST2 receptor, is a chromatin-associated nuclear factor in vivo. Proc Natl Acad Sci USA. 2007;104:282–7. [PMC free article] [PubMed]
29. Kumar S, McDonnell PC, Lehr R, et al. Identification and initial characterization of four novel members of the interleukin-1 family. J Biol Chem. 2000;275:10308–14. [PubMed]
30. Smith DE, Renshaw BR, Ketchem RR, Kubin M, Garka KE, Sims JE. Four new members expand the interleukin-1 superfamily. J Biol Chem. 2000;275:1169–75. [PubMed]
31. Lin H, Ho AS, Haley-Vicente D, et al. Cloning and characterization of IL-1HY2, a novel interleukin-1 family member. J Biol Chem. 2001;276:20597–602. [PubMed]
32. Kumar S, Hanning CR, Brigham-Burke MR, et al. Interleukin-1F7B (IL-1H4/IL-1F7) is processed by caspase-1 and mature IL-1F7B binds to the IL-18 receptor but does not induce IFN-gamma production. Cytokine. 2002;18:61–71. [PubMed]
33. Ferrari D, Pizzirani C, Adinolfi E, et al. The P2X7 receptor: a key player in IL-1 processing and release. J Immunol. 2006;176:3877–83. [PubMed]
34. Dinarello CA, Fantuzzi G. Interleukin-18 and host defense against infection. J Infect Dis. 2003;187(Suppl. 2):S370–84. [PubMed]
35. MacKenzie A, Wilson HL, Kiss-Toth E, Dower SK, North RA, Surprenant A. Rapid secretion of interleukin-1beta by microvesicle shedding. Immunity. 2001;15:825–35. [PubMed]
36. Andrei C, Margiocco P, Poggi A, Lotti LV, Torrisi MR, Rubartelli A. Phospholipases C and A2 control lysosome-mediated IL-1 beta secretion: Implications for inflammatory processes. Proc Natl Acad Sci USA. 2004;101:9745–50. [PMC free article] [PubMed]
37. Sims JE, Acres RB, Grubin CE, et al. Cloning the interleukin 1 receptor from human T cells. Proc Natl Acad Sci USA. 1989;86:8946–50. [PMC free article] [PubMed]
38. Sims JE. IL-1 and IL-18 receptors, and their extended family. Curr Opin Immunol. 2002;14:117–22. [PubMed]
39. McInnes IB, Gracie JA, Leung BP, Wei XQ, Liew FY. Interleukin 18: a pleiotropic participant in chronic inflammation. Immunol Today. 2000;21:312–5. [PubMed]
40. Wang P, Meinhardt B, Andre R, et al. The interleukin-1-related cytokine IL-1F8 is expressed in glial cells, but fails to induce IL-1beta signalling responses. Cytokine. 2005;29:245–50. [PubMed]
41. Vos JB, van Sterkenburg MA, Rabe KF, Schalkwijk J, Hiemstra PS, Datson NA. Transcriptional response of bronchial epithelial cells to Pseudomonas aeruginosa: identification of early mediators of host defense. Physiol Genomics. 2005;21:324–36. [PubMed]
42. Trajkovic V, Sweet MJ, Xu D. T1/ST2 − an IL-1 receptor-like modulator of immune responses. Cytokine Growth Factor Rev. 2004;15:87–95. [PubMed]
43. Dinarello CA. An IL-1 family member requires caspase-1 processing and signals through the ST2 receptor. Immunity. 2005;23:461–2. [PubMed]
44. Colotta F, Re F, Muzio M, et al. Interleukin-1 type II receptor: a decoy target for IL-1 that is regulated by IL-4. Science. 1993;261:472–5. [PubMed]
45. 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]
46. Yanagisawa K, Takagi T, Tsukamoto T, Tetsuka T, Tominaga S. Presence of a novel primary response gene ST2L, encoding a product highly similar to the interleukin 1 receptor type 1. FEBS Lett. 1993;318:83–7. [PubMed]
47. Yanagisawa K, Naito Y, Kuroiwa K, et al. The expression of ST2 gene in helper T cells and the binding of ST2 protein to myeloma-derived RPMI8226 cells. J Biochem (Tokyo) 1997;121:95–103. [PubMed]
48. Takezako N, Hayakawa M, Hayakawa H, et al. ST2 suppresses IL-6 production via the inhibition of IkappaB degradation induced by the LPS signal in THP-1 cells. Biochem Biophys Res Commun. 2006;341:425–32. [PubMed]
49. Bartold PM, Marshall RI, Haynes DR. Periodontitis and rheumatoid arthritis: a review. J Periodontol. 2005;76:2066–74. [PubMed]
50. Marotte H, Farge P, Gaudin P, Alexandre C, Mougin B, Miossec P. The association between periodontal disease and joint destruction in rheumatoid arthritis extends the link between the HLA-DR shared epitope and severity of bone destruction. Ann Rheum Dis. 2006;65:905–9. [PMC free article] [PubMed]
51. Firestein GS. Evolving concepts of rheumatoid arthritis. Nature. 2003;423:356–61. [PubMed]
52. Pihlstrom BL, Michalowicz BS, Johnson NW. Periodontal diseases. Lancet. 2005;366:1809–20. [PubMed]
53. Bartold PM, Narayanan AS. Molecular and cell biology of healthy and diseased periodontal tissues. Periodontol 2000. 2006;40:29–49. [PubMed]
54. Karouzakis E, Neidhart M, Gay RE, Gay S. Molecular and cellular basis of rheumatoid joint destruction. Immunol Lett. 2006;106:8–13. [PubMed]
55. Westacott CI, Whicher JT, Barnes IC, Thompson D, Swan AJ, Dieppe PA. Synovial fluid concentration of five different cytokines in rheumatic diseases. Ann Rheum Dis. 1990;49:676–81. [PMC free article] [PubMed]
56. Kay J, Calabrese L. The role of interleukin-1 in the pathogenesis of rheumatoid arthritis. Rheumatology (Oxford) 2004;43(Suppl. 3):iii2–9. [PubMed]
57. Milner JM, Cawston TE. Matrix metalloproteinase knockout studies and the potential use of matrix metalloproteinase inhibitors in the rheumatic diseases. Curr Drug Targets Inflamm Allergy. 2005;4:363–75. [PubMed]
58. Graves DT, Cochran D. The contribution of interleukin-1 and tumor necrosis factor to periodontal tissue destruction. J Periodontol. 2003;74:391–401. [PubMed]
59. Kornman KS, Page RC, Tonetti MS. The host response to the microbial challenge in periodontitis: assembling the players. Periodontol 2000. 1997;14:33–53. [PubMed]
60. Cho ML, Jung YO, Moon YM, et al. Interleukin-18 induces the production of vascular endothelial growth factor (VEGF) in rheumatoid arthritis synovial fibroblasts via AP-1-dependent pathways. Immunol Lett. 2006;103:159–66. [PubMed]
61. Johnson RB, Serio FG. Interleukin-18 concentrations and the pathogenesis of periodontal disease. J Periodontol. 2005;76:785–90. [PubMed]
62. Orozco A, Gemmell E, Bickel M, Seymour GJ. Interleukin-1beta, interleukin-12 and interleukin-18 levels in gingival fluid and serum of patients with gingivitis and periodontitis. Oral Microbiol Immunol. 2006;21:256–60. [PubMed]
63. 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]
64. Smeets TJ, Kraan MC, Versendaal J, Breedveld FC, Tak PP. Analysis of serial synovial biopsies in patients with rheumatoid arthritis: description of a control group without clinical improvement after treatment with interleukin 10 or placebo. J Rheumatol. 1999;26:2089–93. [PubMed]
65. Leung BP, Xu D, Culshaw S, McInnes IB, Liew FY. A novel therapy of murine collagen-induced arthritis with soluble T1/ST2. J Immunol. 2004;173:145–50. [PubMed]
66. Suchett-Kaye G, Morrier JJ, Barsotti O. Interactions between non-immune host cells and the immune system during periodontal disease: role of the gingival keratinocyte. Crit Rev Oral Biol Med. 1998;9:292–305. [PubMed]
67. Andrian E, Grenier D, Rouabhia M. Porphyromonas gingivalis–epithelial cell interactions in periodontitis. J Dent Res. 2006;85:392–403. [PubMed]
68. Gemmell E, Seymour GJ. Immunoregulatory control of Th1/Th2 cytokine profiles in periodontal disease. Periodontol 2000. 2004;35:21–41. [PubMed]
69. Cutler CW, Jotwani R. Antigen-presentation and the role of dendritic cells in periodontitis. Periodontol 2000. 2004;35:135–57. [PubMed]
70. Lee DM, Friend DS, Gurish MF, Benoist C, Mathis D, Brenner MB. Mast cells: a cellular link between autoantibodies and inflammatory arthritis. Science. 2002;297:1689–92. [PubMed]
71. Gemmell E, Carter CL, Seymour GJ. Mast cells in human periodontal disease. J Dent Res. 2004;83:384–7. [PubMed]
72. Fleischmann RM, Tesser J, Schiff MH, et al. Safety of extended treatment with anakinra in patients with rheumatoid arthritis. Ann Rheum Dis. 2006;65:1006–12. [PMC free article] [PubMed]
73. Cohen S, Hurd E, Cush J, et al. Treatment of rheumatoid arthritis with anakinra, a recombinant human interleukin-1 receptor antagonist, in combination with methotrexate: results of a twenty-four-week, multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2002;46:614–24. [PubMed]
74. Hoffman HM, Firestein GS. Anakinra for the treatment of neonatal-onset multisystem inflammatory disease. Nat Clin Pract. 2006;2:646–7. [PubMed]
75. Linton SD. Caspase inhibitors: a pharmaceutical industry perspective. Curr Top Med Chem. 2005;5:1697–717. [PubMed]
76. Stack JH, Beaumont K, Larsen PD, et al. IL-converting enzyme/caspase-1 inhibitor VX-765 blocks the hypersensitive response to an inflammatory stimulus in monocytes from familial cold autoinflammatory syndrome patients. J Immunol. 2005;175:2630–4. [PubMed]
77. Davis CN, Mann E, Behrens MM, et al. MyD88-dependent and -independent signaling by IL-1 in neurons probed by bifunctional Toll/IL-1 receptor domain/BB-loop mimetics. Proc Natl Acad Sci USA. 2006;103:2953–8. [PMC free article] [PubMed]
78. Assuma R, Oates T, Cochran D, Amar S, Graves DT. IL-1 and TNF antagonists inhibit the inflammatory response and bone loss in experimental periodontitis. J Immunol. 1998;160:403–9. [PubMed]
79. Graves DT, Delima AJ, Assuma R, Amar S, Oates T, Cochran D. Interleukin-1 and tumor necrosis factor antagonists inhibit the progression of inflammatory cell infiltration toward alveolar bone in experimental periodontitis. J Periodontol. 1998;69:1419–25. [PubMed]
80. Delima AJ, Oates T, Assuma R, et al. Soluble antagonists to interleukin-1 (IL-1) and tumor necrosis factor (TNF) inhibits loss of tissue attachment in experimental periodontitis. J Clin Periodontol. 2001;28:233–40. [PubMed]
81. Greenstein G, Polson A. The role of local drug delivery in the management of periodontal diseases: a comprehensive review. J Periodontol. 1998;69:507–20. [PubMed]
82. Taylor JJ, Preshaw PM, Donaldson PT. Cytokine gene polymorphism and immunoregulation in periodontal disease. Periodontol 2000. 2004;35:158–82. [PubMed]

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

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

Recent Activity

    Your browsing activity is empty.

    Activity recording is turned off.

    Turn recording back on

    See more...