IL-18 in autoimmunity: review

ARTICLE

Auteur(s) : Diana Boraschi¹, Charles A Dinarello²

¹Laboratory of Cytokines, Unit of Immunobiology, Institute of Biomedical Technologies, National Research Council, CNR, Area della Ricerca di S. Cataldo, via G. Moruzzi 1, I-56124 Pisa, Italy
²Division of Infectious Diseases, University of Colorado Health Sciences Center, Denver, CO 80262, USA

Mechanisms of innate immunity in the initiation of autoimmunity

Immune activation is initiated in response to invading/stressful events of different origin (both exogenous and endogenous). The innate immune system discriminates between self and alien/abnormal molecular patterns and mounts the first set of inflammatory and defence responses to eliminate the unrecognised element(s), and to initiate the slower and more specific adaptive response. The first interaction between the host and the stress elements (viruses, bacteria, foreign particles, trauma) occurs through the interaction with host cellular sensing structures, in the first place the receptors of the TLR/IL-1R family. This is an important class of receptors involved in the initiation of the inflammatory response and of the innate immune reactions. These receptors share a common signalling pathway and include the TLR receptor family (Toll-like receptors; at least ten different chains in humans), and the IL-1R/IL-18R superfamily. TLR are germ-line, encoded receptors that recognise different microbial structures of bacterial, viral, fungal, and protozoal origin (LPS, lipopeptide, dsRNA, flagellin, CpG, etc.) as well as endogenous, stress-related proteins (heat shock proteins 60 and 70, fibrinogen), thereby triggering responses and activating inflammatory reactions. TLR are mainly expressed by myeloid cells (macrophages), although their presence has been described in T lymphocytes and in several other cells and organs [1]. The IL-1R/IL-18R superfamily includes the receptors for the inflammatory/immunoenhancing cytokines IL-1 and IL-18 [2-4], for the regulatory cytokine IL-33 [5-7], and for a series of orphan receptors, including the putatively inhibitory receptors TIR8/SIGIRR [8-10], and RP105 [11, 12].

Macrophages are among the first cells which are recruited to the site of inflammation and come in contact with invading micro-organisms or foreign agents. Macrophages are versatile, plastic cells, which respond to environmental signals with diverse functions. Classical macrophage activation in response to microbial products (e.g., LPS) and interferon-γ (IFN-γ) has long been recognised and gives rise to potent effector macrophages (M1), which kill microorganisms and tumour cells and produce proinflammatory cytokines and chemokines (including IL-12, TNF-α, IL-1, IL-6, IL-8, MIP-1α). More recently, it has been shown that anti-inflammatory molecules, such as glucocorticoid hormones, IL-4, IL-13 and IL-10, are more than simple inhibitors of macrophage activation, in that they induce a distinct activation pathway (alternatively activated macrophages) [13, 14]. Alternative macrophage activation with IL-4 and IL-13 induces M2 macrophages, which can regulate inflammatory responses and adaptive Th1 immunity, scavenge debris, and promote angiogenesis, tissue remodelling and repair [15, 16]. Classically and alternatively activated (polarised) macrophages have been referred to as M1 and M2, in analogy with the Th1/Th2 dichotomy in T cell responses.

M1 or M2 polarised macrophages differ in terms of receptor expression, cytokine and chemokine production, and effector function. Differential cytokine production characterises polarised macrophages. The M1 phenotype includes IL-12 and TNF-α, while M2 macrophages typically produce IL-10, the IL-1 receptor antagonist (IL-1Ra) and the type II IL-1 receptor (IL-1RII). Differential production of chemokines, which attract Th1 versus Th2 or T regulatory cells, integrates M1 and M2 macrophages in circuits of amplification and regulation of polarised T cell responses. The microenvironment thus influences macrophage activation and their subsequent functions.

In this light, genetic and environmental conditions that promote M1/Th1 polarisation and inhibit M2/Th2 regulatory activity may contribute to the establishment of a chronic inflammatory condition. This may develop into autoimmunity following triggering events (e.g., an infection or trauma) that would induce an autoimmune adaptive response, through mechanisms of molecular mimicry.

M1/Th1–M2/Th2–M17/Th17 network and IL-18

The unravelling of the molecular basis of dysregulated IL-18 overproduction and activity in autoimmune diseases will help to define novel therapeutic targets to limit pathological IL-18 excess. In particular, the correlation of the TLR/IL-1R expression pattern in macrophages with their activation state and IL-18 production capacity, and analysis of macrophage polarisation and IL-18 production and activity in autoimmune states would allow:

• – definition of the role of innate immunity receptors in the regulation of IL-18 production and activity in autoimmune diseases;
• – identification of novel targets to re-program macrophage polarisation/activity towards anti-inflammatory regulatory balancing.

Identification of the anomalies leading to excessive IL-18 production by polarised macrophages in autoimmune patients, and the relevance of TLR triggering in this excessive activation would allow us to devise ways to bias macrophage polarisation or to re-direct the activity of already polarised macrophages toward homeostatic control of IL-18 activation. Also, members of the TLR/IL-1R family may be identified as possible targets for novel therapeutic treatments aimed at inhibiting the excessive IL-18 production at the basis of autoimmune stimulation.

Cytokines in autoimmune diseases: pathological versus pathogenic role

In experimental animal models and in human disease, CD4⁺ T cells play a central role, and both Th1 and Th2-related cytokines are apparently involved in maintaining autoimmune disturbances [23]. More recent findings also indicate a major role in chronic and destructive inflammatory/autoimmune pathologies for Th17 cells [17, 18]. A major pathogenic role is attributed to Th1- and Th17-related cytokines in many autoimmune conditions, particularly those involving chronic inflammation. In addition, Th1 cytokines also sustain autoimmune activation by expanding the pathological T cell clones.

By examining the autoimmune role of Th1-related cytokines, a central pathological effect has been described for the inflammatory Th1-dependent cytokine IFN-γ. For instance, in murine lupus, the ratio of IFN-γ- to IL-4-secreting cells (i.e. the Th1/Th2 ratio) increases with disease progression [24]. Administration of IFN-γ exacerbates the disease in humans and mice [25-28], whereas mice deficient in IFN-γ or IFN-γR develop a less acute disease and have slower disease progression [29-31]. The characteristic pathology-associated double negative (CD4^- CD8^-) T cells and autoantibodies are absent in IFN-γARRAY(0x70c624)deficient mice [32]. In IFN-γR-deficient mice, the renal damage is dramatically reduced [29, 31]. Other studies indicate that IFN-γ accounts for the fatal kidney disease in lpr mice [33, 34]. In EAE, a severe experimental demyelinating disease in rats and mice resembling human multiple sclerosis, IFN-γ and Th1 activation apparently play a major role in the pathological progression [32, 35].

IFN-γ-inducing cytokine IL-18

IL-18 receptors

The IL-18Rα chain can bind with low affinity another molecule of the IL-1 cytokine family, i.e. IL-1F7 [20], a binding that however does not recruit the accessory chain IL-18Rβ, and therefore which does not initiate IL-18Rβ-dependent signalling. That IL-18Rα could be activated by ligands other than IL-18, possibly using a different co-receptor, is suggested by recent data in an experimental model of autoimmune encephalitis, in which deletion of the IL-18 gene did not change susceptibility to disease induction, whereas deletion of the IL-18Rα gene made mice resistant [69]. Since mice do not express IL-1F7, another IL-18-like ligand able to activate IL-18Rα for initiation of autoimmune-related inflammation is currently being sought.

IL-18 binding protein

IL-18BP is not a soluble form of the membrane-bound IL-18Rα, although it has many characteristics of a soluble receptor similar to the IL-1 type II decoy receptor [72]. Unlike all members of the IL-1 receptor family, which have three Ig-like domains in the extracellular receptor segment, IL-18BP has only one Ig-like domain. It seems that the transmembrane and the first two extracellular domains of the ancestral IL-18 receptor were deleted during evolution. The only amino acid identity with the IL-18Rα chain and IL-18BP is found in the third Ig domain of the α chain [73]. There is limited amino acid homology between IL-18BP and the IL-1 type II decoy receptor. In fact, IL-18BP is similar biologically to the IL-1 decoy receptor in that its function is primarily to bind and neutralise the ligand rather than act as a ligand passer.

The human IL-18BP gene is located on chromosome 11q13. Using Northern blot analysis, IL-18BP is highly expressed in spleen and the intestinal tract, both immunologically active tissues. There are four isotypes of human IL-18BP and two isotypes of murine IL-18BP [19]. These isotypes are formed by alternate mRNA splicing of the respective genes. A single copy of the IL-18BP gene exists for humans, mice and rats [74]. Only those isoforms that retain the intact Ig domain are biologically functional, by neutralising IL-18 [19]. For example, human IL-18BP has four isotypes termed IL-18BPa, b, c and d. Only IL-18BPa and IL-18BPc have the intact Ig domain and neutralise IL-18 [19]. The other two isoforms, although they are produced in humans, do not bind and do not neutralise IL-18. However, the mRNA splicing that creates these isoforms is not a haphazard event in that the spliced mRNA has an open reading frame, which results in the same carboxyl terminal for all isoforms. It is possible that IL-18BP isoform b and d bind another member of the IL-1 family. The mouse has two isoforms, IL-18BPc and IL-18BPd. Murine IL-18BPc and IL-18BPd isoforms, possessing the identical Ig domain, also neutralise > 95% murine IL-18. However, murine IL-18BPd, which shares a common C-terminal motif with human IL-18BPa, also neutralises human IL-18 [19].

The sites for binding of IL-1 to the IL-1 receptor type I were used to model the binding of IL-18 to IL-18BP [19]. Modelling predicted a large mixed electrostatic and hydrophobic binding site in the Ig domain of IL-18BP, which could account for its high affinity binding to the ligand. By mutational analysis, two residues in IL-18, glutamic acid at position 35 and lysine at position 89, were found to be important both for binding to IL-18Rα and subsequent biological activity [73, 75], and for binding to IL-18BP and subsequent neutralisation [73].

The regulation of IL-18BP gene expression appears to be via IFN-γ [76]. In a human colon carcinoma epithelial cell line, IFN-γ induced gene expression and release of IL-18BPa. The increase in IL-18BP was also observed in a variety of intestinal cell lines and in a human keratinocyte cell line. The histone deacetylase inhibitor sodium butyrate suppressed IFN-γ-induced IL-18BP gene and protein expression [76]. The promoter for IL-18BP has been described as including two IFN-γ responsive elements [77]. Thus, like other genes encoding cytokine inhibitors (soluble receptors, receptors antagonists and binding proteins), the cytokine itself or a related cytokine induces its own negative regulator in a feed-back loop. Therefore, in a Th1 response, the production of IL-18-dependent IFN-γ contributes to the suppression of IFN-γ by increasing the production of IL-18BP.

The serum levels of IL-18BPa in a cohort of healthy subjects as determined by a specific ELISA were 2.15 ± 0.15 ng/mL (range 0.5-7 ng/mL) [70]. In patients with sepsis and acute renal failure, the levels rose to 21.9 ± 1.44 ng/mL (range 4-132 ng/mL), due to increased production and not to renal retention. Using the law of mass action and knowing the dissociation constant of IL-18BP to IL-18, total IL-18 and free IL-18 were calculated. Total IL-18 in healthy individuals was 64 ± 17 pg/mL and approximately 85% was in the free form [70]. Total IL-18 and IL-18BPa were both elevated in sepsis patients upon admission (1.5 ± 0.4 ng/mL and 28.6 ± 4.5 ng/mL, respectively). At these levels, most of the IL-18 is bound to IL-18BPa, however the remaining free IL-18 in sepsis patients is still higher than in healthy individuals. One can conclude from these studies that IL-18BPa considerably inhibits circulating IL-18 in sepsis. Nevertheless, exogenous administration of IL-18BP may further reduce circulating IL-18 activity.

The relative gene expression of the IL-18-neutralising (a and c) and non-neutralising (b and d) isoforms of IL-18BP was studied in Crohn’s disease during active phases of the disease [78]. Intestinal endothelial cells and macrophages were the major source of IL-18BP within the submucosa, similar to what was observed in cultured human endothelial cells and peripheral blood monocytes. Gene expression, as measured by steady state mRNA levels for IL-18BP as well as the IL-18BP protein, were elevated in intestinal biopsies from patients with active disease [78]. Unbound IL-18BP isoforms a and c and inactive isoform d were present in specimens from patients with active disease as well as in tissues from control patients. The IL-18BP isoform b was not detected. Elevated IL-18BP has been described in several autoimmune diseases including rheumatoid arthritis [46, 79-81], in hepatitis C treated with IFN-α [82] and in patients with chronic liver diseases [83].

IL-18Rα- and IL-18BP-binding cytokine IL-1F7

Inhibitory receptors TIR8/SIGIRR and RP105

TIR8/SIGIRR is a unique receptor of the IL-1R/IL-18R superfamily which, at variance with other members of the family, encompasses a single Ig-like domain in its extracellular portion [92]. The intracellular domain of TIR8/SIGIRR has the highest similarity to the intracellular adapter MyD88 among members of the TLR/IL-1R family [93]. TIR8/SIGIRR does not interact with IL-1α, IL-1β or IL-1Ra, and its intracellular domain is unable to transduce signals [92]. On the other hand, TIR8/SIGIRR apparently plays a central role in the down-regulation of inflammation mediated by TLR/IL-1R. Indeed, TIR8/SIGIRR-deficient mice and cells are more susceptible to stimulation with IL-1, IL-18 and TLR agonists (LPS, CpG oligonucleotides), whereas TIR8/SIGIRR-overexpressing cells were less susceptible to IL-1 and IL-18 stimulation [9, 10]. TIR8/SIGIRR expression is ubiquitous; however, it is preferentially expressed by epithelial cells (kidney, gut, liver) and is possibly involved in the control of intestinal inflammation [8, 10]. On the other hand, TIR8/SIGIRR is poorly expressed in leukocytes and cannot be induced by a series of inflammatory/anti-inflammatory stimuli [8]. Notably, expression of TIR8/SIGIRR in the mouse was significantly decreased in every organ/cell following in vivo administration of LPS [8]. The mechanism by which TIR8/SIGIRR down-regulates TLR/IL-1R-mediated activation is possibly based on the ability of the TIR-containing intracellular domain of TIR8/SIGIRR to compete for the adapter MyD88 and the signalling intermediate TRAF6, thus removing them from the signal transduction pathway of TLR/IL-1R [9]. More recently, with the use of different deletion mutants of TIR8/SIGIRR it has been shown that while for inhibition of TLR4 signalling only the intracellular TIR-containing domain of TIR8/SIGIRR was necessary, the presence of the extracellular Ig-like domain was also required for inhibiting IL-1R signalling, possibly through interference with the interaction between IL-1R and IL-1RAcP [94].

RP105 (CD180) is a transmembrane receptor protein first identified in murine B cells and involved in B cell proliferation and protection from apoptosis [95]. The extracellular portion of RP105 is a leucine-rich repeat domain structurally similar to that of TLR, implying a role in pathogen sensing, in particular in mediating LPS effects on B cells [96, 97] in concert with the accessory molecule MD-1 [98, 99]. A possible down-regulatory role of RP105 can be hypothesized on the basis of a series of experimental evidence. In humans, anti-inflammatory M2-biased macrophages (tumour-associated macrophages generated in vitro) showed up-regulation of mRNA and protein expression for both RP105 and MD-1 [100]. In autoimmune patients with lupus, Sjögren’s syndrome, and dermatomyositis, there is a significant increase in the population of RP105-negative B cells, which are responsible of autoantibody production [101-104]. Finally, recent data indicate that RP105, in concert with MD-1, can down-modulate TLR4/MD-2- and IL-1R-mediated activation by a still undefined mechanism [11, 12].

Receptor T1/ST2 and its ligand IL-33

Intracellular NOD-like receptors

Mutations in another protein of the NLR family, NALP3, are apparently involved in systemic inflammatory diseases, a series of autosomal dominant, severe pathologies characterised by persistent and generalised inflammation. These diseases include the Muckle-Wells syndrome (characterised by recurrent fevers, leukocytosis, cold-urticaria, painful arthropathies, serum amyloid A and CRP elevations, chronic conjuctivitis, uveitis, rashes, death due to renal amyloidosis), the chronic infantile neurological cutaneous and articular (CINCA) syndrome and the neonatal onset multisystem inflammatory disease (NOMID) (both characterised by intermittent fevers, chronic sterile meningitis, uveitis, sensorineural hearing loss, urticarial skin rash, deforming arthritis), and the familial cold autoinflammatory syndrome (FCAS) (urticarial skin rash, arthropathies, fever, leukocytosis, serositis). These diseases are all due to gain-of-function/loss-of-inhibition mutations in the NACHT nucleotide-binding site domain of NALP3 [136, 161-163]. NALP3 (cryopyrin) displays an N-terminal PYR effector binding domain, which interacts with the PYR domain of the adapter protein ASC, which in turn activates caspase-1 maturation after homotypic CARD-CARD interaction. Disease-related mutations in NALP3 cause de-regulation of NALP3 signalling which induces persistent activation of caspase-1, with subsequent increase in the production of caspase-1-dependent inflammatory cytokines (IL-1, and possibly IL-18) and establishment of the chronic inflammatory disease [130, 131, 136, 162, 164]. Very interestingly, the clinical symptoms of diseases due to increased or poor control of caspase-1 activity (CIAS, Muckle-Wells syndrome, adult onset Still’s disease, systemic onset juvenile idiopathic arthritis) often include skin rashes and/or pruritic urticaria. This is likely due to the fact that caspase-1 is also responsible for the maturation of IL-33, which through T1/ST2, activates Th2 responses, IgE production, and mast cell degranulation. A schematic representation of the NALP3 inflammosome is shown in ( figure 3 ).

IL-18 in autoimmunity

Multiple sclerosis

In human multiple sclerosis, there are reports that disease activity correlates with elevated circulating and CSF levels of IL-18 and caspase-1. In addition, IL-18 positive cells have been observed in demyelinating lesions [171-181].
Table 1 Reduction in autoimmune and/or inflammatory disease severity upon neutralisation of endogenous IL-18

Myasthenia gravis

Rheumatoid arthritis

IL-18 also plays a role in collagen-induced arthritis (CIA) [189-191]. IL-18 was injected into DBA-1 mice immunised with collagen in incomplete Freund’s adjuvant. There was an increase in the erosive and inflammatory component of the condition [192]. Using mice deficient in IL-18, CIA was less severe compared to wild-type controls [190]. Histological evidence of decreased joint inflammation and destruction was observed. Levels of bovine collagen-induced IFN-γ, TNF-α, IL-6 and IL-12 from spleen cell cultures were decreased in IL-18-deficient mice. Thus, there is likely a pathological role for IL-18 in CIA. However, it should be noted that IL-18 can also have a beneficial effect, as serum anti-collagen antibody levels are significantly reduced in the IL-18-deficient mice.

Blocking of IL-18 was used in CIA models [193-195]. Wild-type DBA-1 mice were treated with either neutralising antibodies to IL-18 or the IL-18BP after clinical onset of disease. The therapeutic efficacy of neutralising endogenous IL-18 was assessed using different pathological parameters of disease progression. The clinical severity in mice undergoing CIA was significantly reduced after treatment with either IL-18 inhibitor [195]. Attenuation of the disease was associated with histological evidence of reduced cartilage erosion. The decreased cartilage degradation was further documented by a significant reduction in the levels of circulating cartilage oligomeric matrix protein (an indicator of cartilage turnover). Both IL-18 inhibitory strategies efficiently slowed disease progression, but only anti-IL-18 antibody treatment significantly decreased an established synovitis. Serum levels of IL-6 were significantly reduced with both neutralising strategies. In vitro, neutralising IL-18 resulted in a significant inhibition of TNF-α, IL-6, and IFN-γ secretion by macrophages [195].

Mice with established CIA (21 days after the primary immunisation with collagen) were treated for 3 weeks with murine IL-18BP as a fusion protein with the Fc portion of murine IgG1 [194]. Both the clinical disease activity scores and the histological scores of joint damage were reduced by 50%. Proliferation of collagen-stimulated spleen and lymph node cells, as well as the change in serum levels of IgG1 and IgG2a antibodies to collagen, were also decreased. Cell sorting analysis showed a decrease in spleen NK cells and an increase in CD4⁺ T cells. The production of IFN-γ, TNF-α, and IL-1β in cultured spleen cells was reduced. The steady state mRNA levels of IFN-γ, TNF-α, and IL-1β in isolated joints were likewise decreased. Thus, the mechanisms of IL-18BP inhibition of CIA include reduction in cell-mediated and humoral immunity to collagen as well as a decrease in production of proinflammatory cytokines in the spleen and joints. In CIA of BB rats, administration of IL-18 exacerbated arthritic symptoms, whereas anti-IL-18 neutralising antibodies attenuated CIA [196].

Employing an adenoviral vector containing the murine IL-18BP, intra-articular over-expression of IL-18BP significantly reduced the incidence of CIA in treated knee joints [193]. Affected knee joints of IL-18BP-treated mice showed less severe arthritis, with reduced cellular infiltration and less bone erosion. Reduction in cartilage loss was also observed in treated mice. IgG1 anti-collagen type II antibodies were similar to those in the control vector group.

In experiments with mice deficient in IL-18 or in IL-12p40 (lacking both IL-12 and IL-23), antigen-induced arthritis could develop in IL-18-deficient mice as well as in wild type animals, whereas no disease symptoms or antibodies to methylated BSA were evident in mice lacking IL-12p40 [197]. Additional studies with IL-12p35-deficient mice (lacking IL-12 only) and with IL-23p19–deficient animals (lacking IL-23 only) showed that only IL-23-deficient mice were resistant to disease induction [198]. Thus, the role of IL-18 (as well as IL-12) in experimental arthritis appears to be redundant, as compared to the key role for the IL-12p40 cytokine IL-23.

In human rheumatoid arthritis (including juvenile RA, adult-onset Still’s disease, and psoriatic arthritis), IL-18 is present at increased levels in serum and in the rheumatoid synovium, as well as in the bone marrow [79-81, 192, 199-220]. Rheumatoid subcutaneous nodules have the features of Th1 granulomas, with abundant expression of inflammatory cytokines including IFN-γ and IL-18 [221]. Polymorphisms in the promoter region of the IL-18 gene have been found associated with adult onset Still’s disease, RA, and juvenile arthritis [219-226]. IL-18 bioactivity in affected joints of patients with rheumatoid arthritis has been reported to correlate with disease activity [202, 227, 228]. IL-18 is mainly present as precursor protein, but the mature active form is also abundantly detected in macrophages and synovial fibroblasts. IL-18Rα and β receptor chains are found expressed on patients’ T lymphocytes, macrophages, and synoviocytes [79, 192, 202, 229, 230]. Elevated levels of IL-18BP are also present [46, 79, 80]. Synovial tissue from 29 patients with rheumatoid arthritis has been studied using specific staining for IL-18. IL-18 was detectable in 80% of the patients, in both the lining and sublining of synovial tissues from knees. There was a strong correlation between IL-18 and IL-1β expression but less with TNF-α staining [210]. Moreover, IL-18 expression correlated with macrophage infiltration and local inflammation scores. IL-18 staining also correlated with the erythrocyte sedimentation rate, a biomarker of systemic inflammation. Of considerable interest was the observation that in patients with co-expression of IL-18 and IL-12, there were also greater levels of IL-17 [231]. Blocking of endogenous IL-17 with specific inhibitors resulted in a protective inhibition of bone destruction [231-233]. Furthermore, IL-18 can inhibit chondrocyte proliferation and induce production of stromelysin and the inflammatory enzymes iNOS and COX-2, and promote cartilage degradation and glycosaminoglycan release [234]. IL-18 was also found to be able to induce production of serum amyloid A in RA synoviocytes, and to be responsible for acute liver failure in adult onset Still’s disease [235, 236]. Moreover, IL-18 participates in anomalous macrophage activation in hemophagocytic syndrome, a clinicopathological entity associated with adult onset Still’s disease, juvenile chronic arthritis, and possibly lupus erythematosus [237]. It is therefore conceivable to hypothesize a role for IL-18 in the maintenance of the destructive autoimmune and inflammatory processes of rheumatoid diseases, perhaps also by regulating the activities of IL-1β, TNF-α, IFN-γ, and IL-17. Indeed, treatments that ameliorate rheumatoid pathology concomitantly decrease IL-18 production [238]. The possibility of targeting IL-18 in the treatment of arthritis and more generally of chronic inflammatory diseases, is therefore receiving increasing attention [192, 239-249].

Autoimmune uveitis and Behcet’s disease

In human Behcet’s disease, a strong Th1-skewed response is apparently associated with disease severity. Elevated expression of IL-18 is found in serum, skin lesions, and pulmonary lavage fluid, and increased IL-18 production was observed in bronchoalveolar cells upon in vitro stimulation [210, 253-256]. Although no particular polymorphism in the IL-18 promoter gene could be associated with disease sucsptibility, a clear correlation was found between a particular genotype and the risk of developing ocular lesions [257].

Psoriasis

Autoimmune thyroiditis

Systemic lupus erythematosus, Sjögren syndrome, and autoimmune myopathies

Inflammatory bowel disease (IBD) and Crohn’s disease

In human Crohn’s disease, ulcerative colitis, and coeliac disease, increased levels of IL-18 are found in serum, and IL-18, IL-18R chains, and active caspase-1 are increased in chronically inflamed mucosa as compared to early lesions or to normal colonic mucosa [350-362]. Increased IL-18 is evident in mucosal epithelial cells, but is also due to the increase in IL-18-producing DC-SIGN⁺ mucosal DC in Crohn’s patients [363]. Moreover, IL-18 is a potent proliferative stimulus for intestinal mucosal lymphocytes of Crohn’s patients, which, at variance with normal mucosal lymphocytes, show upregulation of the IL-18R chains and are therefore constitutively susceptible to IL-18 activation [339, 364, 365]. Polymorphisms in the promoter and/or coding region of the IL-18 gene have been found to be associated with either increased susceptibility to Crohn’s disease and ulcerative colitis, or to disease severity to varying degrees depending on the population cohort [366-370].

Levels of the IL-18 natural inhibitor IL-18BP are also increased in the plasma of patients with Crohn’s disease and ulcerative colitis [78, 360]. This mechanism of control of IL-18 activity however, does not appear to be effective, as the overall levels of free active IL-18 (i.e. not bound and inhibited by IL-18BP) are still signficantly higher in Crohn’s patients [360]. That IL-18BP is an important player in controlling intestinal damage is suggested by data from experimental models. The increased severity of experimental colitis in IRF-1-deficient mice is associated with decreased levels of colon IL-18BP [348], while the gut lesions in experimental colitis are decreased by administration of IL-18BP [333].

Intestinal inflammation and damage in experimental colitis is associated with an increase in active caspase-1 in the tissue [340, 371, 372]. It is interesting to note that intestinal parasites such as Entamoeba histolitica cause intestinal damage through proteases with caspase-1 activity [373]. Agents that induce apoptosis of colonic epithelial cells concomitantly increase active caspase-1, and inhibition of caspase-1 activity concomitantly inhibits mucosal cell death [374, 375]. Association of Crohn’s disease with loss-of-function mutantions in the gene of NOD2/CARD15, an intracellular protein involved in the caspase-1-activating inflammasome in macrophages, further underlines the importance of caspase-1 products such as IL-18 in the pathogenesis of the disease [143, 144, 148-155, 376, 377]. Treatments that provide therapeutic benefits in Crohn’s patients (e.g. anti-TNF-α antibodies) re-establish appropriate apoptosis of mucosal lymphocytes by increasing the pro-apoptotic caspase pathway [378]. It is notable that therapy-induced increase of caspase-3, which has a major role in lymphocyte apoptosis, is concomitantly expected to decrease the levels of active IL-18, as casapse-3 is the main IL-18 degrading enzyme [379]. Biological therapies targeting IL-18 and other inflammatory cytokines mainly produced by macrophages, are being developed for more effective treatment of IBD [380-383].

Autoimmune type I diabetes (IDDM)

In human IDDM, elevated IL-18 levels can be detected in high-risk individuals, before the development of the disease [406], whereas in patients there is a correlation between IL-18 levels and autoantibody status [407]. As in mice, the human gene for IL-18 maps to an interval, on chromosome 9, where the diabetes susceptibility locus Idd2 resides [408].

Although many of the autoimmune effects of IL-18 in different models and clinical situations are mediated through IFN-γ, and are amplified by IL-12, in some experimental models a direct pathological role for IL-18 has been described. However, IL-18 cannot be considered as an exclusively Th1 cytokine, as its presence may be unrelated to that of IFN-γ. Indeed, IL-18 takes part in the Th17 responses by amplifying the IL-17 production of polarised Th17 cells in synergy with IL-23, thus contributing to the destructive inflammation in several chronic inflammatory, autoimmune diseases [18]. On the other hand, IL-18 can act as a Th2 cytokine in some circumstances [397]. Indeed, in the presence of IL-4 and IL-2, IL-18 can induce significant production of the Th2 cytokines IL-4 and IL-13 by Ag-stimulated T cells, whereas IFN-γ is produced in the absence of IL-4 [409, 410]. Moreover, IL-18R is present on mast cells and basophils, which produce large amounts of IL-4 and IL-13 in response to IL-18 and IL-3 [411]. Thus, IL-18 has been found to play a dual role in Th2-dependent responses such as in helminthic infections and allergic asthma in the mouse. Together with IL-12, IL-18 can suppress IgE production, Th2 cell development, lung hyper-reactivity and eosinophil infiltration, by biasing the immune response to allergen towards Th1 [397, 412, 413]. Moreover, IL-18 deletion could enhance pulmonary eosinophil infiltration [414, 415]. On the other hand, administration of IL-18 induced eotaxin production and subsequently provoked enhanced eosinophil accumulation in pulmonary lesions, and also induced increased synthesis of Th2 cytokines and IgE [410, 415-418]. Thus, although IL-18 has a major role in inflammatory responses, it can become an anti-inflammatory, Th2-biasing factor depending on the cytokine micro-environment (e.g., presence or absence of IL-12).

IL-18 in metabolic syndrome

Unexpectedly, we observed that IL-18-deficient mice have a markedly increased body weight compared to the wild-type littermates of the same age, and have found that in the absence of IL-18, mice develop several features characteristic of the metabolic syndrome: obesity, insulin resistance and hyperglycemia, lipid abnormalities, atherosclerosis [420]. We reported these pathological conditions associated with the metabolic syndrome in mice deficient in IL-18 or the IL-18Rα chain, as well as in mice transgenic for expression of IL-18BP [420]. These mice, in contrast to wild-type mice, eat several times a day and the increased food intake accounts for the obesity. IL-18 deficiency results in a loss of the circadian regulation of food intake and appetite suppression [420]. Because of the large, constitutively-expressed intracellular pool of the IL-18 precursor, especially in liver cells, additional roles for the cytokine other than those played in innate immunity are suspected, and the loss of appetite control appears to a manifestation of the non-immune mechanisms of IL-18.

Obesity in IL-18-deficient mice was due to accumulation of fat tissue based on increased food intake. IL-18-deficient mice also displayed hyperinsulinemia, consistent with insulin-resistance and hyperglycemia. Further analysis of the glucose metabolism in IL-18-deficient mice showed insulin resistance at the hepatic level causing hyperglycemia in these mice, with enhanced expression of gluconeogenesis genes in the liver. In addition, the molecular mechanisms responsible for the hepatic insulin resistance in the IL-18-deficient mice likely involved defective phosphorylation of STAT3, one of the intracellular pathways activated by IL-18. In contrast, MyD88, which mediates a second pathway of activation by IL-18 receptor, was not involved in this process. Recombinant IL-18 reversed hyperglycemia in IL-18-deficient mice through activation of STAT3 phosphorylation. These findings demonstrate a new role of the cytokine IL-18 in the homeostasis of energy intake and insulin sensitivity.

Role of IL-18 in the loss of insulin-producing β-cells

Deficiency in IL-18 and IL-18Rα reveal distinctly opposing phenotypes

Alternate signaling of IL-18Rα

The divergence of responses between IL-18Rα- and IL-18-deficient cells is unexplained. More likely, the data suggest the existence of an IL-18-independent inhibitory pathway that converges with the IL-18 pathway at the IL-18Rα. Accordingly, in cells deficient in the receptor, a putative inhibitory signal, along with the pro-inflammatory IL-18 signal pathway, is absent. Gutcher et al. also provided clear evidence that an IL-18-independent engagement of IL-18Rα exists [69]. In murine experimental autoimmune encephalomyelitis (EAE), IL-18-deficient mice are susceptible to disease progression whereas IL-18Rα-deficient mice are protected. As such, these investigators concluded that there are two distinct pathways converging on the IL-18R: one signal requires IL-18 and the other involves an unknown ligand.

The study comparing islet survival in IL-18- and 18Rα-deficient mice differs from the EAE model in several aspects. Islets from mice deficient in IL-18 or IL-18Rα implanted into a wild-type animal allow for responses of an intact immune system to the genetically altered cells. In the EAE, altered immune system responses are inherent to the knock-out gene. Additionally, in the transplanted islet, early responding cells, such as macrophages, most probably mediate damage; the EAE model provides insights into mechanisms of cell-mediated, autoimmune-processes. Nevertheless, with striking similarity to the islet transplantation data, deficiency in IL-18Rα chain confers an opposite phenotype to that observed in IL-18 deficiency.

Whether the convergence upon the IL-18Rα chain involves a second ligand or a novel receptor accessory chain is presently unknown. IL-1F7, a member of IL-1 family with significant sequence homology with IL-18, binds to IL-18BP and IL-18Rα chain [20, 86]. Upon binding to IL-18Rα, IL-1F7 does not induce IFN-γ production and exhibits no apparent competition with IL-18 [20]. The combination of IL-18BP and IL-1F7 results in greater inhibition of IL-18 activity compared to IL-18BP alone, conferring on IL-1F7 the property of a naturally occurring modulator of IL-18 activity [20]. For any signal in the IL-1 family of receptors to occur, an accessory chain is recruited, the binding of which in this case would result in inhibition of IL-18 activity. Whether the accessory chain is the established IL-18Rβ chain or a novel receptor chain is yet undetermined. However, it was reported that mixing IL-1F7 with soluble IL-18Rα and IL-18Rβ chains did not result in a ternary complex, as formed in the presence of IL-18 and the same receptor subunits. Therefore, we speculate that the accessory receptor chain recruited for IL-1F7 is novel. This model provides a mechanism by which lack of the IL-18Rα chain results in the loss of a negative signal, accompanied by the appearance of a heightened inflammatory response.

Pathogenic role of IL-18 in autoimmunity

The confirmation of the pathogenic role of IL-18 in the development of the autoimmune syndrome was obtained using a vaccination approach to inhibit the excess production of endogenous IL-18. A cDNA vaccination strategy was designed, with an expression plasmid carrying the gene for the IL-18 precursor. Vaccination was performed in young lpr/lpr mice, which at the time had no signs of the disease, but which already showed increased IL-18 levels in various organs. After vaccination in the muscle tissue, the IL-18 plasmid synthesized the IL-18 protein, and consequently an anti-IL-18 response was generated. Why an antibody response against an autologous protein occurs after cDNA vaccination is not completely clear. One cannot rule out that the autoimmune-prone background of the recipient plays a role. The anti-IL-18 response triggered by vaccination significantly reduced the activity of IL-18 in the organs of lpr/lpr mice, and thus disease development was significantly delayed and was less severe, as judged by the pathological parameters of lymphadenopathy, renal damage, proteinuria, and early death [293]. Decrease in disease progression can also be detected when vaccination is performed in older mice with overt disease (P Bossù and D Neumann, unpublished observations). On the basis of the results obtained with anti-IL-18 vaccination, and following the notion that IL-18 acts in synergy with IL-12 in inducing Th1 inflammatory responses having a central role in several autoimmune syndromes, another study was carried out in lpr/lpr mice, by vaccinating animals with cDNA for both IL-12 and IL-18 [423]. Concomitant administration of cDNA coding for the two cytokines induced a potent inhibition of lymphadenopathy and splenomegaly (the most striking characteristics of the disease), and practically abolished the kidney damage and proteinuria. In addition, the strong inflammatory infiltrate evident in lungs of lpr/lpr mice was absent in IL-18/IL-12-vaccinated animals.

To confirm the pivotal role of IL-18 in the autoimmune pathogenesis, IL-18Rα-deficient lpr/lpr mice were shown to survive longer and have significant reduction in renal pathology. Skin lesions, lymphadenopathy, and lung pathology were also diminished in IL-18Rα-deficient lpr/lpr mice [424]. In agreement with results obtained with cDNA vaccination and with analysis of gene expression in kidney (Martinelli et al., in preparation), IL-18Rα-deficient lpr/lpr mice did not show a decrease in autoantibody production or in end-organ disease, stressing the hypothesis that IL-18 is mainly involved in the initiation of the autoimmune syndrome rather than in mediating its destructive, downstream effects [425].

Thus, taking the above data together, IL-18 plays an essential role in the pathogenic process in murine lupus. Further evidence for a pathogenic role of IL-18 in autoimmunity comes from IL-18-deficient mice (e.g., diabetes following induction with streptozotocin, collagen-induced arthritis) [190, 394]. In addition, IL-18BP inhibits the hyperglycemia and insulitis that precedes streptozotocin-induced diabetes [395]. IL-18 is upregulated during progression from insulitis to diabetes in TcR transgenic mice treated with cyclophosphamide [388]. In human situations, there are increased levels of IL-18 in individuals at high risk of developing IDDM [406].

Therapeutic approaches to inhibit IL-18 in autoimmunity

IL-18BP is in clinical trials for a variety of autoimmune diseases including rheumatoid arthritis. A divalent fusion protein of human IL-18BP linked human IgG1 Fc (IL-18BP:Fc) binds and neutralises human, mouse, and rat IL-18 with a dissociation constant of 0.3-5 nM. Using E. coli-derived endotoxin, with a lethal dose of 90%, IL-18BP:Fc administered 10 minutes prior to the endotoxin, significantly reduced mortality [426]. IFN-γ levels were also reduced in these mice. Because of the long plasma half-life of Fc fusion protein, IL-18BP:Fc reduced endotoxin-induced IFN-γ when administered 6 days before the endotoxin challenge. IL-18BP:Fc reduced hepatic injury as well as expression of Fas [426]. IL-18BP:Fc also decreased granuloma formation and production of the chemokines MIP-1α and MIP-2. As shown previously using anti-mouse IL-18 [427], IL-18 mediates the hepatic damage caused by intravenously injected Concanavalin A [426]. Fas ligand expression as well as liver damage induced by Pseudomonas aeruginosa exotoxin A or by anti-Fas agonistic antibody were also reduced by IL-18BP [426]. IL-18BP:Fc reduces the severity of CIA [194]. In other experimental models of chronic inflammatory autoimmune pathologies, the IL-18BP:Fc construct was found to ameliorate disease onset and progression, through inhibition of IL-18 [333, 396].

Inhibition of caspase-1 or of caspase-1-activating inflammosomes is a therapeutic option that is being actively pursued [428-431]. Orally active caspase-1 inhibitors went into clinical trials for their efficacy as anti-inflammatory drugs (such as VX-740, pralnacasan, and VX-765). While a rheumatoid arthritis trial with pralnacasan was suspended after detection of long-term liver abnormalities in treated animals, VX-765 is in trials for the treatment of psoriasis and is reported to be effective in blocking the hyperreactivity to inflammatory stimulation of monocytes from FCAS patients, who have excessive caspase-1 activation due to a mutation in the criopyrin gene [432].

Although very promising, each of these approaches have their drawbacks. Repeated administration of recombinant antibodies or proteins (also when fully human) may elicit an immune response that would reduce their therapeutic efficacy. This is a circumstance that occurs with most therapeutic proteins, even of autologous origin, in particular in autoimmune patients. On the other hand, each IL-18 blocking strategy, including vaccination, must be carefully optimised in order to obtain an effective immune response against excess endogenous IL-18, which should be reduced without being abolished. In fact, since IL-18 is important for the adequate Th1-dependent reactions and for the balance with Th2 responses, its complete down-regulation could lead to immunosuppression with severe consequences. Indeed, increased susceptibility to certain infections has been reported in patients undergoing anti-cytokine therapies (reviewed in [433]). As an example, anti-TNF-α therapies in patients with rheumatoid arthritis, although not inducing an obvious immunosuppressed phenotype, increase the incidence or induced re-activation of tuberculosis [433-444]. Studies on the role of cytokines in mycobacterial infections underline the central role of TNF-α and IFN-γ in host reaction to mycobacterial infection [445, 446]. Since IL-18 is the major inducer of IFN-γ, its role in the anti-mycobacterial response likely depends on IFN-γ induction [447, 448]. In patients with active tuberculosis infections, the levels of IL-18 and IFN-γ in serum, pleural effusions and alveolar macophages are significantly increased [445, 449-453]. Administration of IL-18 DNA or transfected cells in mice caused enhanced IFN-γ production and a potent anti-mycobacterial response [454-456]. Likewise, IL-18 transgenic mice show increased resistance to mycobacterial infection [457]. Conversely, mice susceptible to mycobacterial infection produced significantly less IL-18 as compared to genetically resistant mice [458]; IL-18 knock-out mice were defective in IFN-γ production in response to mycobacterial infection and developed non-necrotic granulomas [459, 460].

Conclusions and future perspectives

Acknowledgements

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423 Neumann D, Tschernig T, Popa D, Schmiedl A, Pérez de Lema G, Resch K, Martin MU. Injection of IL-12 and IL-18 encoding plasmids ameliorates the autoimmune pathology of MRL/Mp-^Tnfrsf6lpr mice: synergistic effect on autoimmune symptoms. Int Immunol 2006; (in press).

424 Kinoshita K, Yamagata T, Nozaki Y, Sugiyama M, Ikoma S, Funauchi M, Kanamaru A. Blockade of IL-18 receptor signaling delays the onset of autoimmune disease in MRL-Fas^lpr mice. J Immunol 2004; 173: 5312.

425 Lin L, Peng SL. Interleukin-18 receptor signaling is not required for autoantibody production and end-organ disease in murine lupus. Arthritis Rheum 2005; 52: 984.

426 Faggioni R, Cattley RC, Guo J, Flores S, Brown H, Qi M, Yin S, Hill D, Scully S, Chen C, et al. IL-18-binding protein protects against lipopolysaccharide-induced lethality and prevents the development of Fas/Fas ligand-mediated models of liver disease in mice. J Immunol 2001; 167: 5913.

427 Faggioni R, Jones-Carson J, Reed DA, Dinarello CA, Feingold KR, Grunfeld C, Fantuzzi G. Leptin-deficient (ob/ob) mice are protected from T cell-mediated hepatotoxicity: role of TNF-α and IL-18. Proc Natl Acad Sci USA 2000; 97: 2367.

428 Randle JC, Harding MW, Ku G, Schonharting M, Kurrle R. ICE/Caspase-1 inhibitors as novel anti-inflammatory drugs. Expert Opin Investig Drugs 2001; 10: 1207.

429 Siegmund B. Interleukin-1β converting enzyme (caspase-1) in intestinal inflammation. Biochem Pharmacol 2002; 64: 1-8.

430 Faubel S, Edelstein CL. Caspases as drug targets in ischemic organ injury. Curr Drug Targets Immune Endocr Metabol Disord 2005; 5: 269.

431 Linton SD. Caspase inhibitors: a pharmaceutical industry perspective. Curr Top Med Chem 2005; 5: 1697.

432 Stack JH, Beaumont K, Larsen PD, Straley KS, Henkel GW, Randle JCR, Hoffman HM. 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.

433 Dinarello CA. Anti-cytokine therapeutics and infections. Vaccine 2003; 21(Suppl 2): S24-S34.

434 Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J, Schwieterman WD, Siegel JN, Braun MM. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med 2001; 345: 1098.

435 Gomez-Reino JJ, Carmona L, Valverde VR, Mola EM, Montero MD. Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors may predispose to significant increase in tuberculosis risk: a multicenter active-surveillance report. Arthritis Rheum 2003; 48: 2122.

436 Nahar IK, Shojania K, Marra CA, Alamgir AH, Anis AH. Infliximab treatment of rheumatoid arthritis and Crohn’s disease. Ann Pharmacother 2003; 37: 1256.

437 Campbell IK, Roberts LJ, Wicks IP. Molecular targets in immune-mediated diseases: the case of tumour necrosis factor and rheumatoid arthritis. Immunol Cell Biol 2003; 81: 354.

438 Zhang Y. Persistent and dormant tubercle bacilli and latent tuberculosis. Front Biosci 2004; 9: 1136.

439 Toussirot E, Wendling D. The use of TNF-α blocking agents in rheumatoid arthritis: an overview. Expert Opin Pharmacother 2004; 5: 581.

440 Mobley JL. Is rheumatoid arthritis a consequence of natural selection for enhanced tuberculosis resistance? Med Hypotheses 2004; 62: 839.

441 Rychly DJ, DiPiro JT. Infections associated with TNF-α antagonists. Pharmacotherapy 2005; 25: 1181.

442 Botsios C. Safety of tumour necrosis factor and interleukin-1 blocking agents in rheumatic diseases. Autoimmun Rev 2005; 4: 162.

443 Calabrese L. The yin and yang of TNF inhibitors. Cleve Clin J Med 2006; 73: 251.

444 Furst DE, Wallis R, Broder M, Beenhouwer DO. TNF antagonists: different kinetics and/or mechanisms of action may explain differences in the risk for developing granulomatous infection. Semin Arthritis Rheum 2006; (Epub ahead of print).

445 Jo EK, Park JK, Dockrell HM. Dynamics of cytokine generation in patients with active pulmonary tuberculosis. Curr Opin Infect Dis 2003; 16: 205.

446 Salgame P. Host innate and Th1 responses and the bacterial factors that control Mycobacterium tuberculosis infection. Curr Opin Immunol 2005; 17: 374.

447 Sugawara I. Interleukin-18 (IL-18) and infectious diseases, with special emphasis on diseases induced by intracellular pathogens. Microbes Infect 2000; 2: 1257.

448 Biet F, Locht C, Kremer L. Immunoregulatory functions of interleukin 18 and its role in defense against bacterial pathogens. J Mol Med 2002; 80: 147.

449 Yamada G, Shijubo N, Shigehara K, Okamura H, Kurimoto M, Abe S. Increased levels of circulating interleukin-18 in patients with advanced tuberculosis. Am J Respir Crit Care Med 2000; 161: 1786.

450 Vankayalapati R, Wizel B, Weis SE, Samten B, Girard WM, Barnes PF. Production of interleukin-18 in human tuberculosis. J Infect Dis 2000; 182: 234.

451 Morosini M, Meloni F, Marone BA, Paschetto E, Uccelli M, Pozzi E, Fietta A. The assessment of IFN-γ and its regulatory cytokines in the plasma and bronchoalveolar lavage fluid of patients with active pulmonary tuberculosis. Int J Tuberc Lung Dis 2003; 7: 994.

452 Inomata S, Shijubo N, Kon S, Maeda M, Yamada G, Sato N, Abe S, Uede T. Circulating interleukin-18 and osteopontin are useful to evaluate disease activity in patients with tuberculosis. Cytokine 2005; 30: 203.

453 Kwiatkowska S, Szkudlarek U, Luczynska M, Nowak D, Zieba M. Elevated exhalation of hydrogen peroxide and circulating IL-18 in patients with pulmonary tuberculosis. Respir Med 2006; (Epub ahead of print).

454 Kim SH, Cho D, Kim TS. Induction of in vivo resistance to Mycobacterium avium infection by intramuscular injection with DNA encoding interleukin-18. Immunology 2001; 102: 234.

455 Kremer L, Dupre L, Wolowczuk I, Locht C. In vivo immunomodulation following intradermal injection with DNA encoding IL-18. J Immunol 1999; 163: 3226.

456 Chung SW, Choi SH, Kim TS. Induction of persistent in vivo resistance to Mycobacterium avium infection in BALB/c mice injected with interleukin-18-secreting fibroblasts. Vaccine 2004; 22: 398.

457 Kinjo Y, Kawakami K, Uezu K, Yara S, Miyagi K, Koguchi Y, Hoshino T, Okamoto M, Kawase Y, Yokota K, et al. Contribution of IL-18 to Th1 response and host defense against infection by Mycobacterium tuberculosis: a comparative study with IL-12p40. J Immunol 2002; 169: 323.

458 Kobayashi K, Nakata N, Kai M, Kasama T, Hanyuda Y, Hatano Y. Decreased expression of cytokines that induce type 1 helper T cell/interferon-γ responses in genetically susceptible mice infected with Mycobacterium avium. Clin Immunol Immunopathol 1997; 85: 112.

459 Takeda K, Tsutsui H, Yoshimoto T, Adachi O, Yoshida N, Kishimoto T, Okamura H, Nakanishi K, Akira S. Defective NK cell activity and Th1 response in IL-18-deficient mice. Immunity 1998; 8: 383.

460 Sugawara I, Yamada H, Kaneko H, Mizuno S, Takeda K, Akira S. Role of interleukin-18 (IL-18) in mycobacterial infection in IL-18-gene-disrupted mice. Infect Immun 1999; 67: 2585.

461 Fantuzzi G, Banda NK, Guthridge C, Vondracek A, Kim SH, Siegmund B, Azam T, Sennello JA, Dinarello CA, Arend WP. Generation and characterization of mice transgenic for human IL-18-binding protein isoform a. J Leukoc Biol 2003; 74: 889.

462 Netea MG, Fantuzzi G, Kullberg BJ, Stuyt RJ, Pulido EJ, McIntyre Jr. RC, Joosten LA, Van der Meer JW, Dinarello CA. Neutralization of IL-18 reduces neutrophil tissue accumulation and protects mice against lethal Escherichia coli and Salmonella typhimurium endotoxemia. J Immunol 2000; 164: 2644.

463 Melnikov VY, Ecder T, Fantuzzi G, Siegmund B, Lucia MS, Dinarello CA, Schrier RW, Edelstein CL. Impaired IL-18 processing protects caspase-1-deficient mice from ischemic acute renal failure. J Clin Invest 2001; 107: 1145.

464 Pomerantz BJ, Reznikov LL, Harken AH, Dinarello CA. Inhibition of caspase 1 reduces human myocardial ischemic dysfunction via inhibition of IL-18 and IL-1β. Proc Natl Acad Sci USA 2001; 98: 2871.

465 Dinarello CA. Novel targets for interleukin 18 binding protein. Ann Rheum Dis 2001; 60(Suppl 3): iii18.

466 Raeburn CD, Dinarello CA, Zimmerman MA, Calkins CM, Pomerantz BJ, McIntyre Jr. RC, Harken AH, Meng X. Neutralization of IL-18 attenuates lipopolysaccharide-induced myocardial dysfunction. Am J Physiol Heart Circ Physiol 2002; 283: H650.

467 Dai C, Krantz SB. Interferon γ induces upregulation and activation of caspases 1, 3, and 8 to produce apoptosis in human erythroid progenitor cells. Blood 1999; 93: 3309.