ARTICLE
INTRODUCTION
Several findings indicate that an appropriate combination of cytokines
and immunocompetent cells is required to mount a successful immune response.
More than ten years ago, T. Mosmann et al. demonstrated that T
helper (Th) cells can be divided in two populations with contrasting and
cross-regulating cytokine profiles [1]. The distinctive cytokine production
profile of Th1 and Th2 cells is associated with distinct immune functions.
Th1 cells, which produce IL-2 and IFN-gamma, are involved in inflammatory
and cell-mediated immune responses, whereas Th2 cells, which produce IL-4,
IL-5, IL-6, IL-10 and IL-13, are associated with humoral and allergic
responses. Dysregulation of the Th1/Th2 balance is often observed in uncontrolled
infectious diseases, cancers, allergy or autoimmunity [2]. The differentiation
of naive Th0 cells into Th1 or Th2 subsets is influenced by several parameters
such as the nature of the antigen, the type of antigen-presenting cell
(APC) [3], the expression of costimulatory molecules [4] and local cytokine
production [5]. Only a few cytokines (i.e. IFN-gamma and IL-12)
are involved in the commitment of undifferentiated Th0 cells to becoming
Th1 cells. IL-18, previously called IFN-gamma inducing factor (IGIF),
has been recently added to the short list of Th1-promoting cytokines [6,
7]. IL-18 is related to the IL-1 family in terms of its structure, receptor
family and signal transduction pathways [8]. Mainly produced by APC [9,
10], IL-18 acts in synergy with IL-12 for Th1 differentiation [11-13].
It also exerts pro-inflammatory properties by inducing the production
of IL-1beta, TNF-alpha, chemokines [14], nitric oxide and prostaglandins
[15]. The pleiotropic activities of IL-18 suggest an important role of
this cytokine in the triggering and polarization of the immune response.
This review summarizes the recent advances in the understanding of IL-18
structure, processing, receptor expression and immunoregulatory functions,
and deals with the role of IL-18 in tumours, infections, and autoimmune
and inflammatory diseases.
INTERLEUKIN-18
AND ITS RECEPTOR
The IL-18 protein
IL-18 was originally described as an IFN-gamma-inducing factor in mice
primed with Propionibacterium acnes (P. acnes) and challenged by
lipopolysaccharide (LPS) [6, 9]. The murine IL-18 gene maps to chromosome
9 [16] and the human IL-18 gene is located on chromosome 11q22 [17]. Murine
and human IL-18 gene sequences encode 192 and 193 amino acid precursor
proteins, respectively [7]. Amino acid sequence homologies between hIL-18
and IL-1alpha (12%) and IL-1beta (19%) have been demonstrated, as well
as a similarity in their conformational structure, inasmuch as the positions
of beta sheets, involved in the binding of IL-1 to their receptors, are
conserved.
Like IL-1beta, IL-18 is synthesised as a biologically inactive, 24 kDa
precursor molecule lacking a signal peptide (Figure
1). Cleavage into an active mature 18 kDa molecule requires intracellular
cysteine protease IL-1beta converting enzyme (ICE), also known as caspase-1
[18, 19]. Caspases belong to a protease family which plays a pivotal role
in inflammation and apoptotic cell death [20]. The major role of caspase-1
(ICE) in the processing of IL-18 has been demonstrated in ICE-deficient
mice. These mice treated with P. acnes and LPS produce low levels
of IFN-gamma, which is restored by injection of mature IL-18 [21]. More-over,
in vitro, nitric oxide molecules, known to be potent inhibitors
of caspase activity, prevent the release of both active IL-1beta and IL-18
from macrophages [22]. Recently, Dinarello et al. identified a
29 kDa serine esterase, proteinase-3 (PR-3), an extracellular enzyme released
by activated neutrophils, monocytes, endothelial and mast cells, that
cleaves proIL-18 into an active form [23]. Altogether, these results suggest
that proIL-18 can be processed intracellularly as well as extracellularly.
Finally, caspase-3 (CPP32), involved in apoptosis, cleaves both precursor
and mature forms of IL-18 into biologically inactive degraded products
[24], and may constitute a potential down-regulator of IL-18.
Regulation of IL-18 gene expression is unlike that of most other cytokines.
The murine IL-18 gene comprises seven exons distributed over 26 kb. The
promoter activity was detected upstream of two 5'-noncoding exons (exons
1 and 2) in two distinct promoter regions which are TATA-less and not
G+C rich. One promoter activity (upstream of exon 2) is constitutive,
while the other (upstream of exon 1) is up-regulated in activated macrophage
and T cell lines. Moreover, IL-18 mRNA does not contain RNA destabilising
elements (repeat of AUUUA sequences) in the 3' untranslated region, implying
a long half-life for
IL-18 mRNA [25]. Human PBMC and murine spleen cells express a steady-state
IL-18 mRNA and constitutively contain and secrete the IL-18 precursor
[26]. The presence of preformed immature IL-18 allows rapid production
of the mature, active molecule when the cell is activated. Regulation
of IL-18 activity may therefore predominantly occur at the level of processing
rather than at the transcriptional and translational level.
Activated macrophages and Kupffer cells were first described to produce
high levels of IL-18 [6]. Recent data demonstrate that IL-18 is also produced
by dendritic and Langerhans cells [10, 27]. In human haematopoietic cell
lines, IL-18 mRNA expression is predominantly detected in the myelomonocytic
lineage, rarely in B-cells (personal data) and no expression is detected
in T cells. These features support the notion that antigen-presenting
cells (APC) represent the major source of IL-18 production [24] (Table
1). However, IL-18 production is not entirely limited to haematopoietic
cells, as low levels of IL-18 mRNA and protein are observed in murine
keratinocytes, which are rapidly up-regulated following contact with allergen
[28]. In rats, IL-18 mRNA is detected in the adrenal cortex, specifically
in regions that produce glucocorticoids, and in the neurohypophysis, suggesting
a neuro-immunomodulatory role of IL-18 [29]. In the central nervous system,
astrocytes and microglial cells also produce IL-18 [30, 31]. The production
of IL-18 by osteoblasts inhibits osteoclast formation (via GM-CSF
induction) and, in conjunction with IL-1beta, regulates bone density [32].
It has been demonstrated that human articular chondrocytes produce and
respond to IL-18 protein [15]. Finally, we have demonstrated that intestinal
epithelial cells from the oesophagus to the rectum constitutively synthesise
IL-18 protein [33]. IL-18 production is observed in the villi and at the
top of crypts, in the most differentiated cells facing an antigen rich
environment. In contrast, in embryonic intestinal epithelium, with no
exogenous antigen, IL-18 protein is not detected [34], suggesting that
IL-18 could also participate in gut mucosal immunity.
IL-18 receptors
Like most cytokine receptors, the IL-18 receptor (IL-18R) is a heterocomplex
composed of a constitutive ligand binding chain, the alpha chain, originally
described as IL-1 receptor related protein (IL-1Rrp) [35, 36], and an
inducible accessory chain, the beta chain, originally named accessory
protein-like (AcPL) [37]. Human IL-1Rrp and AcPL genes are located in
a region of chromosome 2 shared with the other IL-1 receptor type I genes
[38, 39]. These two chains belong to the IL-1 receptor family and share
the same structural organisation. They are predicted to contain a signal
peptide, an extracellular segment with three immunoglobulin-like domains
(about 340 amino acids), a single transmembrane region, and a cytoplasmic
domain (about 200 amino acids). The cytoplasmic domains of IL-1 and IL-18
receptors share significant homology with a Drosophilia protein Toll,
a number of human Toll-like receptors and plant proteins [39]. A functional
homology between the Toll homology domain (THD) is also described, suggesting
that the IL-1 and IL-18 system evolved from an ancient immune system.
The IL-18 receptor alpha chain (IL-1Rrp) binds IL-18 with low affinity,
whereas the beta chain (AcPL) does not bind IL-18 but increases the affinity
of the receptor and is involved in the signal transduction pathway [40].
The study of human IL-18R expression on peripheral blood mononuclear
cells using a mAb raised against IL-18Ralpha (IL-1Rrp) revealed that most
CD19+ B cells, some CD8+ T cells and NK cells constitutively
express low levels of the alpha chain [41]. This expression is increased
after activation with IL-12 and mitogen. On human CD4+ T cells,
the alpha chain is only expressed after mitogenic stimulation [41] (Table
2). Murine models show that the alpha chain is inducible on T cells after
optimal activation with anti-CD3 plus anti-CD28 and is selectively expressed
on Th1 but not Th2 cells [42-44].
The downstream effectors of IL-18 signalling are closely related to
those involved in the IL-1 transduction pathway [45]. The binding of IL-18
to its receptor induces the recruitment of IL-1 receptor associated kinases
(IRAK) to the receptor complex, which requires an intracellular adapter
molecule, MyD88 [46]. They both interact with TRAF6, inducing activation
of c-Jun NH2-terminal kinase (JNK) and subsequently translocation of NFkappaB
to the nucleus [12] (Figure 2).
The generation of IRAK-deficient mice confirms the important role of this
kinase in IL-18-induced signalling and function in NK and Th1 cells [47].
Other kinases have been implicated in the IL-18 transduction pathway:
p38 MAP Kinase in U1 cells [48], p42 MAPK and p56lck in a murine
Th1 clone [49].
Recently, a secreted IL-18 binding protein (IL-18BP) with IL-18 antagonist
activity was purified and cloned from human urine [50] and from the sera
of mice with endotoxin shock [51]. The IL-18BP gene is located on human
chromosome 11q13, and encodes three splice variants. They share a common
ATG translation start, encode the same 28 amino acid signal peptide and
mature soluble proteins with distinct molecular weights. The most abundant
form described is IL-18BPa cDNA [50], which encodes a 193 amino acid protein
that belongs to the Ig superfamily, and has limited homology with IL-1
type II receptor (IL-1RII) [50]. The genomic sequence of IL-18BP does
not contain any exon coding for a transmembrane domain, suggesting that
this soluble protein is not derived from cleavage of a membrane-bound
receptor. IL-18BP mRNA is constitutively expressed in PBL, spleen, thymus,
colon, small intestine and prostate. In vitro experiments demonstrate
that this protein impairs the Th1 response, abolishes the induction of
IL-18-induced IFN-gamma and IL-8 production and activation of NFkappaB.
These results suggest that IL-18BP acts as a soluble decoy receptor for
IL-18 and inhibits its biological activity [50].
Recent studies revealed that human poxvirus encodes a family of proteins
with homology to IL-18 [50, 52]. These poxvirus proteins are able to bind
IL-18 with high affinity and to inhibit IL-18-mediated INF-gamma production
[52]. The binding of poxvirus proteins to IL-18BP provides a mechanism
to escape to the IL-18 mediated immune response against viruses.
BIOLOGICAL
PROPERTIES OF IL-18
IL-18 and IL-1beta are related to the same family in terms of structure,
processing, receptor family and signal transduction pathways. Like IL-1beta,
IL-18 exerts proinflammatory properties, but this cytokine is also related
to IL-12 in view of its capacity to induce the production of Th1 cytokines
and to enhance cell-mediated immune cytotoxicity (Figure
3).
Implication of IL-18 in Th1 development and
IFN-gamma production
The differentiation of naive CD4+T lymphocytes (Th0) into
Th1 or Th2 effector cells is partly controlled by the cytokines produced
by APC. IL-12 is shown to enhance Th1 development and T cell production
of IFN-gamma [53]. IL-18 induces IFN-gamma production by activated murine
and human T cells, in synergy with IL-12 [11, 13, 44]. The up-regulation
of IL-18Ralpha gene and surface expression by IL-12 may explain its capacity
to increase IL-18-induced IFN-gamma production by T cells [42, 54]. The
synergy between IL-12 and IL-18 could also be explained by the use of
two distinct transduction pathways to trigger IFN-gamma gene transcription
[55]. IL-18 directly induces IFN-gamma promoter activity at the AP-1 site,
whereas IL-12 induces the occupancy of the signal transducer and activator
of transcription (STAT)4 binding site [12]. The combination of both cytokines
activates AP-1 and STAT4 binding sites, as demonstrated in human CD4+
T cells [55, 56].
Although IL-18 is a potent inducer of IFN-gamma production by Th1 cells,
Robinson et al. demonstrated that, unlike IL-12, murine IL-18 does
not induce Th1 development, and confirmed that IL-18 synergizes with IL-12
for this effect [12]. As shown in IL-12-deficient mice [57], IL-18-deficient
mice display a reduced production of IFN-gamma and a defective Th1 cell
response [58]. The generation of mice lacking both IL-18 and IL-12 further
impaired Th1 responses [58]. These results demonstrate the importance
of the in vivo cooperative activity of IL-18 and IL-12 in IFN-gamma
production and Th1 development.
IFN-gamma production in response to IL-18 is not restricted to Th1 cells.
The combination of IL-18 and IL-12 on CD8+ T cells [44, 59],
NK cells [60, 61] and activated B cells [62] induces up-regulation of
the IL-18Ralpha chain and the production of large amounts of IFN-gamma.
Both cytokines enhance IgG2a production and inhibit IL-4-dependent IgE
and IgG1 production by activated B cells [62]. Finally, when stimulated
with IL-18 and IL-12, murine macrophages are also potent IFN-gamma producers
[63].
IL-18 has no effect on Th2 differentiation and related cytokine production,
as IL-18 fails to induce IL-4 and IL-10 production from Th2 cells, even
in combination with IL-12 [11, 13, 44, 55]. Th2 cells do not express IL-18R
mRNA and do not produce IFN-gamma in response to anti-CD3 and IL-18 [42,
43]. Th1 and Th2 cells also differ in responsiveness and receptor expression
for IL-1 family molecules. Th1 cells selectively express IL-18R, whereas
Th2 cells express IL-1R [12]. IL-1 and IL-18 may therefore differentially
amplify Th2 and Th1 effector responses, respectively, and the presence
of IL-18R may be important to distinguish Th1 cells from Th2 cells.
IL-18 enhances the cytotoxic activity of immune
cells
Th1 cell response and NK cell activity are significantly impaired in
IL-18 deficient mice, demonstrating the important role of IL-18 in the
development of an effective cell-mediated immune response.
In response to IL-18 stimulation, murine Th1 (but not Th0 or Th2) clones
selectively enhance FasL-mediated cytotoxicity [64]. In murine mixed lymphocyte
cultures, IL-18 also enhances the development of type I CD8+
effectors T cells with strong allospecific CTL activity and intense IFN-gamma
production, in a CD4+ T cell-dependent manner [59]. IL-18 alone
or, for optimal effect, in combination with IL-2 or IL-12, induces proliferation,
IFN-gamma production and cytotoxicity of murine NK cells [61]. Studies
of perforin-deficient mice or the use of a potent inhibitor of perforin
show that IL-18 and IL-12 directly and independently enhance perforin-mediated
cytotoxic activity of NK cells. However, IL-18, in contrast with IL-12,
does not up-regulate perforin and granzyme transcription, but probably
regulates their functions at the protein level [65]. Moreover, IL-18 increases
the expression and killing mediated by FasL on liver and splenic NK cells
[66, 67]. Finally, IL-18 enhances the killing activity of liver NK-T cells
by a perforin-dependent pathway [68]. The up-regulation by IL-18 of these
two mechanisms of cytotoxicity is in accordance with recent data for NK
and T cells, demonstrating that newly synthesised FasL is located in exocytosis
granules, which contain perforin and granzyme molecules [69].
Proinflammatory properties of IL-18
IL-18 is constitutively produced by APC as a preformed cytokine and
can therefore be rapidly processed into an active form during mounting
of an inflammatory response. The proinflammatory activity of IL-18 is
mediated by the production of inflammatory cytokines, chemokines, nitric
oxide, and prostaglandins and is amplified by IL-18-induced IFN-gamma
production which in turn activates macrophages.
In human unstimulated PBMC, IL-18 induces synthesis of TNF-alpha from
CD4+ T cells and NK cells, and IL-1beta from monocytes/macrophages
[14, 70]. IL-18 also induces IL-6 production by LPS-activated PBMC [14].
IL-18 has chemoattractive properties on polymorphonuclear cells by stimulating
IL-8 production. Chemokines involved in the recruitment of monocytes/macrophages,
macrophage inflammatory protein-1alpha (MIP-1alpha) and monocyte chemotactic
protein-1 (MCP-1) are also produced by IL-18-activated PBMC [70]. This
chemokine synthesis is mediated by NK cells [71] and monocytes/macrophages
[14]. In KG-1 cells, IL-18 enhances the expression of ICAM-1 molecule
[72], suggesting a potent role of IL-18 in the tissue infiltration of
immune cells.
Some anti-inflammatory properties of IL-18 and IL-18-induced molecules
may account for the control of the inflammatory process. In turn, IFN-gamma
production can limit the release of chemokines, such as IL-8 [14]. Activation
of NK cells by IL-12 and IL-18 induces the production of an anti-inflammatory
cytokine, IL-10 [71] that could limit the synthesis of TNF-alpha.
ROLE OF IL-18 IN DISEASE
IL-18 plays a central role in the immune response by acting on Th1 cell
differentiation, cell-mediated cytotoxicity and inflammation. Our investigations
in colonic cancer and Crohn's disease (CD), an inflammatory bowel disease,
together with recent data on infectious and autoimmune diseases, suggest
that inappropriate IL-18 production may be involved in the pathogenesis
of these diseases and may influence the clinical outcome of patients.
Infectious diseases
Administration of anti-IL-18 Abs in mice infected with Salmonella
typhimurium [73] or Yersinia enterocolitica [74] induces a
marked increase in spleen bacterial counts, showing that neutralization
of biologically active IL-18 leads to uncontrolled bacterial infections.
Abolition of IL-18 production may impair the generation of protective
antibacterial immunity, as shown in IL-18-deficient mice infected with
M. bovis and M. tuberculosis [75]. In addition, administration
of anti-IL-18 Abs in mice infected with Cryptococcus neoformans
exacerbates the fungal infection, whereas administration of IL-18 enhances
clearance of the pathogen [76, 77]. The role of IL-18 in viral infections
is more controversial. IL-18 acts together with IFN-alpha, to induce IFN-gamma
production and to control infection with Influenza A virus [78]. IL-18
is also implicated in the immune response against Herpes simplex
virus-1 [79] and Sendai virus [80], while IL-18 stimulates the production
of HIV-1 virus in a chronically HIV-1 infected monocytic cell line [48].
Thus, in bacterial, fungal, and parasitic [81] infections and, to a lesser
extent, in viral infections, abrogation of IL-18 production and the subsequent
down-regulation of IFN-gamma, TNF-alpha and NO production, leads to uncontrolled
infection.
Overproduction of IL-18 in bacterial infection may also be detrimental.
The murine model of BALB/c mice primed with Propionibacterium acnes
(P. acnes) and challenged with LPS, shows the implication of IL-18
in septic shock and acute liver injury [6, 9]. Overexpression of IL-18
in mice liver is followed by induction of IFN-gamma, TNF-alpha and FasL
[82, 83]. Abrogation of IL-18 production (with anti-IL-18 mAbs or in IL-18-deficient
mice) induces down-regulation of IFN-gamma and TNF-alpha production and
complete prevention of FasL-mediated liver injury [9, 58, 84].
These data demonstrate that IL-18 plays a central role in the development
of an efficient immune response against pathogens. Abrogation or overproduction
of IL-18 is detrimental to the control of infectious diseases.
Tumours
Th1 polarization of the immune response has been shown to be a factor
of good prognosis in many types of cancer [85, 86]. IFN-gamma production
promotes immune recognition of tumour cells by enhancing the expression
of MHC molecules and stimulates cytotoxicity of NK cells, T lymphocytes
and macrophages [87]. The presence of IFN-gamma in the serum of patients
with lung cancer [88], and in situ transcription of IFN-gamma in
cervical carcinoma [89] have been shown to be correlated with a favourable
clinical outcome. As IL-18 is an IFN-gamma-inducing cytokine produced
in human colonic mucosa, we wondered whether IL-18 was modulated in human
colonic cancer and investigated the influence of IL-18 modulation in tumour
outgrowth. IL-18 and ICE transcription is decreased or abolished in colonic
cancers [33]. 50% of tumours did not present any IFN-gamma or FasL transcripts,
suggesting impairment of the IL-18-related immune response. This profile
is associated with lymph node and/or hepatic metastases and an unfavourable
clinical outcome. It may also provide a new mechanism of FasL-related
immune escape leading to dissemination of the tumour.
Mice implanted with tumour cells, transfected or coinjected with IL-18,
allowed identification of the immune components responsible for the beneficial
effects of IL-18 production at the tumour site. Rejection of tumour cells
is mediated by NK cells, cytotoxic CD4+ and CD8+
T cells and is associated with the establishment of an antitumour immune
memory [90-92]. The antitumour effects of IL-18 are only marginally impaired
in IFN-gamma or IL-12 gene-disrupted mice [93], suggesting that IL-18
antitumour effects may also involve FasL-mediated cytotoxicity [67] and
inhibition of tumour angiogenesis [94].
Autoimmune and inflammatory diseases
Insulin-dependent diabetes mellitus (IDDM)
Many lines of evidence suggest that a polarized Th1 response is critical
for the initiation and maintenance of autoimmune diseases. IFN-gamma and
IL-12 are elicited in individuals predisposed to insulin-dependent diabetes
mellitus (IDDM). In the non-obese diabetic (NOD) mouse model, upregulation
of IFN-gamma expression correlates with disease onset. The crucial role
of Th1 cells in mediating destruction of beta cell islets has been demonstrated
by the inhibitory effects of anti-IFN-gamma mAbs and the ability of Th1-specific
T cell clones to adoptively transfer diabetes [95]. A potential role of
IL-18 in this murine model is suggested by colocalization of the IL-18
gene and a diabetes susceptibility gene (Idd2) from the NOD mouse in the
same region of chromosome 9 [16] and by increased IL-18 production in
the islets before their destruction [16, 96]. A recent study shows that
the administration of IL-18 during the pre-diabetic phase significantly
decreased the incidence of diabetes in NOD mice [97]. A lower intraislet
infiltration is detected and an impaired progression from Th2 insulitis
to Th1-dependent insulitis is evidenced in IL-18 treated NOD mice [97].
Experimental autoimmune encephalomyelitis (EAE)
Murine EAE is an induced inflammatory and demyelinating disease of the
central nervous system widely used as an animal model for multiple sclerosis.
EAE is partly mediated by autoreactive Th1 cells secreting IFN-gamma in
response to encephalitogenic myelin basic protein (MBP) epitopes [98].
IL-18 mRNA increases during the acute stage of EAE together with a marked
induction of ICE mRNA [99]. In vitro, neutralizing anti-IL-18 mAbs
reduce the T cell production of IFN-gamma in response to MBP epitopes.
Moreover, anti-IL-18 mAbs administered to rats during EAE prevent the
development of lesions. Splenic T cells from IL-18 treated rats cultured
with MBP preferentially produce IL-4, while non-treated cells produce
IFN-gamma and TNF-alpha [100]. Altogether, these results suggest a role
of IL-18 in the early stages of EAE development and potentially in multiple
sclerosis.
Rheumatoid arthritis
Rheumatoid arthritis is characterized by synovial inflammation and cartilage
degradation [101]. In vitro studies show that IL-1beta and TNF-alpha,
released by synoviocytes and chondrocytes, are the principal mediators
of inflammation. Increased IL-18 production has been demonstrated in the
synovium of patients with rheumatoid arthritis [102]. Human articular
chondrocytes produce mature IL-18 [15]. IL-18 inhibits TGF-beta-induced
chondrocyte proliferation, and promotes the expression of genes encoding
inducible nitric oxide synthase (iNOS) and inducible cyclooxygenase (COXII)
[15]. Overexpression of IL-18 in arthritis by articular chondrocytes and
the related production of inflammatory molecules (NO and prostaglandins)
may therefore contribute to cartilage degradation [15].
Crohn's Disease
Crohn's disease (CD) is an inflammatory bowel disease associated with
a polarized Th1 cytokine profile [103]. An increased production of proinflammatory
cytokines, IL-1beta and TNF-alpha [104], and IL-8 chemokine is observed
in CD lesions [105]. Study of the murine model of dextran sulphate sodium-induced
colitis, a model for CD, shows up-regulation of IL-18 mRNA and protein.
Moreover, blocking of IL-18 resulted in improvement of disease activity
[106]. As also observed in recent reports, we demonstrated increased expression
of IL-18 protein in the mucosa of chronic inflamed CD [34, 107-109]. Upregulation
of ICE transcripts [34] and detection of the active form of ICE [108]
are in accordance with the overproduction of a biologically active form
of IL-18 in CD lesions. We identified epithelial cells and macrophages
of lamina propria as the major source of IL-18 production in CD lesions
[34]. Direct evidence of the role of IL-18 in immune disorders of CD lesions
is provided by the study of the cytokine pattern in various stages of
CD lesions. We showed, in chronic lesions, that a marked increase of ICE
transcription, suggesting the presence of IL-18 active form, is associated
with intense synthesis of IL-18-related cytokines (IFN-gamma, IL-1beta,
TNF-alpha and IL-8). By contrast, neither IL-18 nor ICE mRNA are enhanced
in early CD lesions, in comparison with normal colonic tissues, and the
IL-18-related cytokines are not up-regulated [34]. Overproduction of IL-18
may also be involved in the development of ulcerative colitis, another
inflammatory bowel disease [107, 108] (personal data). All these data
strongly suggest the major role played by IL-18 in the initiation and
development of inflammatory bowel diseases.
New insight into the biological activity of IL-18 suggests that this
cytokine plays a key role in the initiation and coordination of the cell-mediated
immune response. This cytokine, that shares functional properties with
IL-1beta and IL-12, acts on Th1 cell differentiation, cellular cytotoxicity
and inflammatory responses, which may explain the major consequences of
IL-18 dysregulation in defective immune defence against pathogens, and
in neoplastic and inflammatory diseases.
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