Download Crossed signals: the role of interleukin-15 and

Rheumatology 2008;47:1269–1277
Advance Access publication 10 July 2008
doi:10.1093/rheumatology/ken257
Signalling, inflammation and arthritis
Crossed signals: the role of interleukin-15 and -18 in autoimmunity
H. P. Carroll1, V. Paunović1 and M. Gadina1
Several cytokines are involved in the complex processes ultimately leading to autoimmune diseases. In a preceding review, we have already
discussed the role of the IL-12 and -17 families of cytokines. This review is focused on IL-15 and -18. Both these molecules have
pro-inflammatory activity and act on many cell types and because of their broad spectrum of activity they play an important role in
autoimmunity and disease pathogenesis. Their biological activity is ultimately regulated by the signalling cascades set into motion within
their target cells. In this second review, we will, once again, describe the signal transduction pathways activated by these two cytokines and
focus on how this relates to the pathogenesis of autoimmune diseases. We will also describe some of the therapeutic approaches that
are being investigated to curtail the pro-inflammatory activities of these two molecules.
KEY WORDS: Inflammation, Cytokines, Autoimmunity, Rheumatoid arthritis, Signal transduction, Janus Kinase–Signal Transducers and Activators of
Transcription pathway, Nuclear factor-B.
exists as two alternatively spliced isoforms, which encode for two
forms of IL-15 protein, a secreted form (48aa) [3] and an intracellular form (non-secretable form) (21aa) which is localized to
both cytoplasmic and nuclear compartments [14].
IL-15 production is induced by a variety of exogenous factors,
including double-stranded RNA, Type I IFN, lipopolysaccharide,
UV irradation, a number of viruses including, herpes simplex virus
and respiratory syncitial virus, and fungal and bacterial agents
such as Candida albicans, Escherichia coli and Staphylococcus
aureus [15–18].
Introduction
The inflammatory reaction observed in autoimmune disease
involves both cellular and soluble players. Pro-inflammatory
cytokines such as the members of the IL-12 and -17 families,
which we have discussed in our previous review [1], are undoubtedly at the centre of the processes which result in unregulated
activation of immune cells. On the other hand, other immunoregulatory cytokines have been demonstrated to have a very
important role. In particular, IL-15, which is critical for the
regulation of lymphocyte homeostasis as well as NK cell development, and IL-18, a potent inducer of IFN- and TNF have also
been shown to have a major role in the events leading to an
excessive inflammatory response. In this review, we have focused
our attention to IL-15 and -18 discussing their complex biological
activity and their signalling cascades in the normal immune
response and in diseases, as well as some of the current therapeutic
approaches targeting these two cytokines.
IL-15: receptor and signalling
IL-15 binds to a heterotrimeric receptor that comprises the same
chain (IL-2R, -15R and CD122) and the common chain
( c; CD132) as the IL-2 receptor. The IL-15 receptor also includes
a cytokine-specific chain, IL-15R chain. IL-15R complex is
expressed on monocytes, DCs, NK, T cells and fibroblasts [19, 20]
(Fig. 1). IL-15R mRNA is expressed in a number of cell types
and tissues, including T, B cells, macrophages, kidney and heart
[21]. IL-15R binds IL-15 with high affinity [22]. It has a short
cytoplasmic domain and an extracellular region containing one
sushi domain (a highly conserved protein binding domain also
known as a glycoprotein 1 motif), which is critical for IL-15
binding [23–25].
IL-15R not only exists as a membrane-bound receptor
but also in soluble form [26, 27]. The transmembrane IL-15R
undergoes specific proteolytic cleavage to generate a soluble
26 kDa protein in mouse and 42 kDa protein in humans [26, 27].
In mice, the generation of soluble form of IL-15R (sIL-15R)
is produced by cleavage of transmembrane IL-15R by TNFconverting enzyme [26]. Shedding of the soluble form of the
receptor may act as a further checkpoint for IL-15 activity. IL-15
has only a single binding site for interaction with IL-15R.
Therefore, the availability of free IL-15 will be reduced by the
presence of this high-affinity, soluble receptor [28]. Competition
with the membrane-bound receptor could result in reduced
IL-15R signalling and therefore reduced biological activity of
IL-15. This is supported by in vivo evidence which suggests that
administration of sIL-15R results in the inhibition of NK
cell proliferation [29] and antigen-specific T-cell responses [30].
Conversely, it has recently been reported that sIL-15R can
convert IL-15 to a superagonist that enhances the IL-15 responses
in CD8þ and NK cells both in vivo and in vitro [28]. It is speculated
that upon sIL-15R binding to IL-15 a conformational change
IL-15
IL-15: structure and production
IL-15 is a 14–15 kDa member of the four -helix cytokine
family with structural similarities to IL-2 [2, 3]. Like IL-2, IL-15
stimulates the proliferation of CD4þ and CD8þ T cells, immunoglobulin M (IgM) or CD40L-treated B cells, as well as the generation and persistence of NK cells [4–9]. However, IL-2 and -15
exhibit major differences in the control of their synthesis and
secretion [5, 10]. IL-2 production is tightly regulated during
transcription, whereas, IL-15 mRNA is constitutively expressed
by a wide variety of human tissues and cell types, including
activated monocytes, macrophages, dendritic cells (DCs), osteoclasts and fibroblasts of the spleen, gingiva and skin [3, 5, 11–13].
Interestingly, the patterns of IL-15 protein and mRNA expression differ greatly, indicating tight control of protein production
at both translational and post-translational levels. IL-15 mRNA
1
Centre for Cancer Research and Cell Biology, Queen’s University Belfast,
Belfast, UK.
Submitted 1 February 2008; revised version accepted 13 June 2008.
Correspondence to: H. P. Carroll, Centre for Cancer Research and Cell Biology,
Queen’s University Belfast, Belfast BT9 7BL, Northern Ireland, UK.
E-mail: [email protected]
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ß The Author 2008. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: [email protected]
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H. P. Carroll et al.
FIG. 1. Schematic representation of the IL-15 receptor and IL-18 receptor complexes and summary of the signal transduction events following ligand binding. The IL-15R
complex consists of IL-2R, -2R and -15R. Upon ligand binding JAK1 and JAK3 are recruited to the - and -cchains, respectively. STAT3 and STAT5 dock to
phosphorylated IL-2R via the SH2 domains are tyrosine phosphorylated, form homo/heterodimers and translocate to the nucleus where they activate gene transcription.
The IL-15R chain recruits TRAF 2 leading to the activation of NF-B. The sIL-15R binds to IL-15 with high affinity. In mast cells, IL-15RX binds with high affinity to IL-15
and results in the activation of JAK2 or Tyk2 even in the absence of the IL-2R and -2R chains leading to the activation of STAT5 or STAT6 and up-regulation of Bcl-XL and
c-Myc expression. IL-18 binds to the IL-18R bringing the two chains of the IL-18 in close proximity. The TIR domains recruit various kinases ultimately leading to the
activation of NF-B and the p38 MAP kinase pathway. IL-18 binding may be inhibited by the presence of IL-18BP that binds to IL-18 with high affinity.
occurs in the cytokine, which enhances its interaction with the
c receptor.
Although IL-15 was originally identified as a soluble cytokine
in tissue culture supernatant of a simian renal epithelial cell line
CV-1/EBNA [3], it has proven difficult to detect in biological
fluids from healthy individuals despite widespread mRNA expression. In fact, evidence now indicates that IL-15 is not normally
secreted but forms stable high-affinity complexes with IL-15R
on the cell surface of antigen presenting cells (APCs) [20]. IL-15,
bound to cell surface IL-15R on APCs, is then presented in trans
to T cells and NK cells expressing the c receptor dimer [20]. IL15 then induces signalling at the interface of the immunological
synapse and contributes to co-stimulatory signals that modify the
cell response [31].
Since the IL-2R and -15R contain the same - and -subunits,
subsequent signal transduction is mediated by the same molecules,
Janus kinases 1 and 3 (JAKs1/3) and Signal Transducer and
Activator of Transcription 3 and 5 (STATs 3/5) [4, 32, 33]. JAK1
is recruited to the IL-2R chain, whereas JAK3 is recruited to the
IL-2R chain (Fig. 1). Additionally, IL-15 triggers several other
signalling pathways, including phosphorylation of the Src-family
of protein tyrosine kinases Lck and Syk, stimulation of the
phosphatidylinositol-3-kinase (PI3-K)/AKT pathway, and stimulation of the Ras/Raf/MAPK pathway leading to the activation
of Fos- and Jun-containing transcription factor complexes [34].
IL-15-mediated T-cell proliferation is also regulated through
FK506-binding protein 12 (FKBP12) activation of p70-S6 kinase.
Moreover, FKBP12 is involved in the pathway leading to the
activation of ERK MAPK downstream of IL-15 [35].
Notably, signalling pathways can also be triggered through
IL-15R. Membrane-associated IL-15R has a short cytoplasmic
tail with no obvious signalling motifs or docking sites, and therefore was thought to have no signalling capabilities. However, the
cytoplasmic domain of IL-15R can recruit TNF receptorassociated factor (TRAF) 2 following IL-15 binding resulting in
nuclear factor-B (NF-B) activation. NF-B is one of the most
FIG. 2. Schematic representation of the target cells of IL-15. IL-15 acts on a wide
range of both immune and non-immune cell types. It is important for protection against apoptosis, supporting proliferation and functional activity of several
immune cells. It is critical for Th1 and Th17 polarization; it induces effector
functions in mast cells, neutrophils, NK cells, B cells, macrophages and DCs.
In non-immune cells, it not only confers protection from apoptosis but it also
induces angiogenesis of endothelial cells.
important regulators of pro-inflammatory gene expression, resulting in the synthesis of cytokines, such as TNF-, IL-1, -6 and -8
[36]. Syk kinase has also been shown to be critical for IL-15R
signalling [37, 38].
IL-15: biological activity
IL-15 is a broad spectrum immune-regulatory cytokine that
supports the survival, proliferation and functional activity of
a number of immune cell types (Fig. 2 and Table 1). Indeed, mice
deficient in IL-15 exhibit depleted NK, NKT, T, CD8þ and
Role of Il-15 and -18 in autoimmunity
TABLE 1. The functional effects of IL-15 on cells of the immune system
Cell type
Th17 cells
CD8 cells
NK cells
B cells
Neutrophils
DCs
Monocytes
Macrophages
Mast cells
Functional Effects
Enhances TCR-mediated proliferation
Critical for development and maintenance of
effector memory cells
Protects from apoptosis
Protects from apoptosis
Promotes cytotoxic activity
Protects from apoptosis
Enhances Ig production by activated B cells
Enhances proliferation and differentiation
Protects from apoptosis
Enhances phagocytosis
Protects from apoptosis
Stimulates functional maturation
Enhances T- and NK-cell simulation by up-regulating
expression of co-stimulatory molecules and IFN-
Enhances phagocytic activity
Stimulates the production of pro-inflammatory cytokines
Supports proliferation
Protects from apoptosis
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of IFN- [58]. IL-15 also inhibits apoptosis of neutrophils by
decreasing expression of pro-apoptotic protein Bax [59] and
increasing expression of anti-apoptotic myeloid cell differentiation
factor-1 [59, 60].
IL-15 can act as a growth factor for mast cells, supporting
their proliferation and preventing their apoptosis through the
up-regulation of Bcl-xL expression [61]. Mast cells use a unique
high-affinity receptor for IL-15 known as IL-15RX (Fig. 1) and
the signalling events following IL-15 binding to this receptor are
different to other cell types. Upon IL-15 binding to IL-15RX
JAK2/STAT5 or Tyk2/STAT6 are activated and this signalling
cascade does not require the presence of the IL-2R- or -chains
[61–63]. Interestingly, mast cells not only express IL-15RX but
also a number of functional isoforms of IL-15R; however, the
relevance of these two high-affinity receptors on mast cells is still
unclear. IL-15 is also a major modulator of non-immune target
cells inducing angiogenesis in endothelial cells and conferring
protection from apoptosis in endothelial cells, fibroblasts, epithelial cells, as well as oesteoclasts (Table 1).
IL-15: role in autoimmunity
memory phenotype T-cell numbers, emphasizing the important
role of IL-15 in lymphocyte subset development [39].
Numerous reports have shown that IL-15 is critical for the
maintenance of long-lasting, high-avidity T-cell responses by
sustaining the survival of CD8þCD44hi memory T cells [6, 40–44].
A recent study has identified a subset of effector memory CD8þ T
cells (IL-7RlowCCR7), which proliferate weakly in response to
TCR stimulation but proliferate in response to IL-15 resulting in
the non-specific expansion of a polyclonal population of effector
memory cells [45]. IL-15-induced proliferation and expansion of
autoantigen-specific CD8þ effector memory T cells could promote
autoimmune responses leading to enhanced pathogenesis of the
disease. Indeed, patients with SLE show increased IL-15 levels and
an expanded CD8þ effector memory T-cell population correlating
with disease severity [46]. IL-15 also enhances the TCR-dependent
proliferation of IL-17-secreting Th cells (Th17) and Th17/Th1
(IL-17 and IFN- producing) cells [47], which are known to play
a role in the development of a number of autoimmune diseases
[1, 48]. Therefore, IL-15-induced expansion of IL-17-producing
T-cell populations may result in enhanced autoimmune activity.
As already mentioned earlier, gene-targeting studies in mice
have demonstrated that IL-15 is essential for the survival, activation and functional activity of NK cells. Mice over-expressing
IL-15 have an expanded NK cell population, which results in
enhanced innate immune reactions [42]. Furthermore, efficient
NK cell killing has recently been shown to be mediated through
the formation of a regulatory synapse with DCs to which IL-15R
on the NK cells accumulates [49].
IL-15 is also critical for the functional maturation of both
macrophages and DCs [50]. IL-15 enhances the phagocytic activity of monocytes and macrophages and induces the production of
pro-inflammatory factors such as IL-8 and MCP-1 [51]. In DCs,
IL-15 up-regulates the expression of co-stimulatory molecules and
IFN-, enhancing the ability of DCs to activate CD8þ cells and
NK cells [15, 52]. In addition, reduced numbers of peripheral DCs
have been observed in IL-15/ and IL-15R/ mice suggesting
a role for IL-15 in DC survival [53].
Interestingly, IL-15/ and -15R/ mice do not present with
any defects in B-cell responses [54, 55]. However, activated B-cell
functions are greatly influenced by IL-15. Activated B cells
proliferate in response to IL-15 and in combination with CD40L
produce IgA, IgG1 and IgM [56]. IL-15 also acts as a survival
factor for activated B cells [57].
In neutrophils, IL-15 is critical for their influx into inflammatory foci during antigen-induced inflammation. In vivo
administration of IL-15 can induce the production of IL-18
within 90 min, resulting in neutrophil influx that is independent
IL-15 is a potent pro-inflammatory cytokine and it has been
demonstrated to play a role in the pathogenesis of a number of
autoimmune diseases. IL-15 is detectable in the serum of patients
with ulcerative colitis [64]. The inflamed mucosa from patients
with IBD expresses increased levels of IL-15 mRNA [65] and
T cells from the lamina propria are more responsive to IL-15 than
control T cells leading to enhanced production of the proinflammatory cytokines TNF- and IFN- [66].
Psoriatic lesions express high levels of IL-15 [67]. In a human
psoriasis xenograft model, the administration of an antibody that
inhibited IL-15 binding to IL-15R resulted in reduced severity of
signs of the disease [68]. Indeed, Zhang et al. [69] report a genetic
association between IL-15 and psoriasis. A haplotype of the
30 UTR region of IL-15 is associated with an increased risk of
psoriasis and increased activity of IL-15.
Patients with multiple sclerosis (MS) have increased numbers of
peripheral blood mononuclear cells (PBMCs) expressing IL-15
mRNA compared with healthy controls [70] and enhanced
expression of IL-15 mRNA has been found in MS-active plaques
[71]. In addition, monocytes from relapsing–remitting patients
have an increased level of membrane-bound IL-15 and their T
cells express high levels of IL-15R, which may contribute to
enhanced IFN- release during MS [72].
Studies have shown that IL-15 can be detected in the serum and
synovial membrane of patients with RA [73–76]. In association
with IL-18, -12 and IFN-, IL-15 has also been detected in synovial membrane derived from patients with JRA [77]. In addition,
IL-15 expressed by fibroblast-like synoviocytes and endothelial
cells, has been shown to cause a marked increase in transendothelial migration of both CD4þ and CD8þ T cells [78]. These data
were supported by the observation that the expression of IL-15
leads to the accumulation of T cells in RA synovial tissues
engrafted into mice with severe combined immunodeficiency [78].
IL-15 enhances synovial T-cell proliferation and cytokine
release. Synovial neutrophils are also activated by IL-15 [5, 79].
Indeed, upon stimulation with IL-15, neutrophils from patients
with RA, but not from healthy donors, produce significant
amounts of IL-18 and other chemotactic factors that may help to
promote chronic inflammation [58].
As mentioned earlier, IL-15 is a potent growth and survival
factor for mast cells. Mast cells make a major contribution to the
pathogenesis of arthritis and are found in abundance in synovial
sections from patients with RA [80]. Studies in mast cell-deficient
mice have highlighted their importance for disease onset as these
mice do not develop joint inflammation and are resistant to
arthritis [81]. It has been proposed that mast cells may be a cellular
link between autoantibodies, the complement system and the
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onset of inflammatory arthritis [81]. Interestingly, mouse mast
cells have been shown to express constitutive and LPS-inducible
IL-15 that is stored intracellularly [82]. Intracellular IL-15 has
been shown to suppress the activity of chymase in mast cells
resulting in decreased production of neutrophil-recruiting chemokines [82]. It is therefore possible that extracellular and
intracellular sources of IL-15 play distinct roles in mast cell
function and consequently in disease pathology.
Targeting IL-15
Several approaches have been used to antagonize the activity of
IL-15 in vivo. These include the administration of soluble murine
IL-15R, neutralizing antibodies and mutated forms of IL-15,
all of which have been successful for the prevention and treatment
of CIA in mice [83, 84].
Two antibodies that inhibit IL-15 activity have been developed
and tested in clinical trials. MikI is a mAb raised against
IL-2/IL-15R subunit that blocks trans-presentation of IL-15 by
APC to target NK and CD8þ T cells [85]. It prolongs primate
cardiac allograft survival [86] and it has also been tested in Phase I
clinical trials in patients with MS, RA, refractory coeliac disease
and HTLV-1-associated tropical spastic paraparesis. However,
it has been argued whether the administration of this antibody
will be effective since its effects are mediated via IL-15 and partial
IL-2 blockade. Indeed, the possibility of inducing autoimmune
phenotype similar to that observed in IL-2-deficient mice has been
suggested as a possible obstacle to the success of this therapy [87].
AMG14 (also known as HuMax-IL-15), a human IgG1 mAb
that binds and neutralizes the activity of both soluble and
membrane-bound IL-15 in vitro has also been tested in humans
[88]. Preliminary results have shown that IL-15 neutralization was
well tolerated and resulted in marked improvements in disease
activity [88]. However, this initial study was not placebo controlled and consequently another multi-centre, randomized, doubleblind, placebo trail was conducted, which reported no significant
alterations in the levels of NK and CD8þ memory T cells [88].
The two major signalling pathways activated by IL-15 are the
NF-B and the JAK–STAT pathways and they have been the
subject of intense research in the search for possible therapeutic
interventions. Activation of NF-B is the major event in the
signalling cascade downstream of the IL-18 receptor and will be
discussed subsequently.
IL-15, like all the c-utilizing cytokine activates JAK3, and
a JAK3 antagonist, CP690 550 has now been developed. This
inhibitor shows nanomolar potency, and has demonstrated good
immunosuppressant activity in a primate model of transplantation
[89]. IL-2 signalling was effectively blocked in animals treated with
this inhibitor, with minimal effects on the number of NK cell
suggesting that IL-15 signalling was possibly only mildly affected.
Nonetheless, clinical studies using CP690 550 are now ongoing
in RA patients and patients with psoriatic lesions [90–92]. In both
these pathologies, good remission rates and dose-dependent
improvements were observed. However, inhibition of JAK2,
which is also non-specifically inhibited by CP690 550, has been
suggested to be the cause of the anaemia observed in patients in
the pre-clinical studies.
In conclusion, IL-15 is an immunoregulatory cytokine which
exhibits pro-inflammatory activity by acting on a wide variety of
cell types. Some of these effects are direct and include Th1 and
Th17 polarization as well as activation of effector cells such as B,
NK, mast cells and neutrophils. Other effects are indirect and
involve the production of other pro-inflammatory cytokines such
as IFN- and IL-17 as well as IL-18. In particular, the induction
of IL-18 in neutrophils is of primary importance for the initial
stages of the inflammatory process and we will now discuss in
detail the effects of this other immunoregulatory cytokine.
IL-18
IL-18: structure and production
IL-18 is a member of the IL-1 superfamily of cytokines and was
initially discovered as an IFN--inducing factor produced by
macrophages stimulated with microbes or microbial products [93].
IL-18 is produced as an inactive 23 kDa precursor that is cleaved
by caspase 1 to form the biologically active 18 kDa species [94].
Proteinase-3, caspase-3, cathepsins and elastase can also cleave the
precursor polypeptide, but this can result in the production of
inactive forms of IL-18 [95–97].
The IL-18 promoter does not contain a TATA sequence
and is constitutively active upstream of exon 2, resulting in the
continuous expression of IL-18 mRNA [98]. Control of IL-18
expression occurs primarily through processing of the procytokine into the active form and its subsequent release.
Not only is IL-18 controlled by cleavage of the pro-cytokine to
the active form, the biological activity of IL-18 is also controlled
by IL-18 binding protein (IL-18BP). IL-18BP has a high affinity
for IL-18 and neutralizes its biological activity [99, 100]. There
are four human isoforms of IL-18BP, which are specific for the
mature active form of IL-18 and their expression is localized to
the spleen and intestinal tract [101]. Interestingly, IL-18BP expression in keratinocytes and intestinal cell lines is up-regulated
in response to IFN- [102]. Therefore, a negative feedback loop
exists for IL-18-induced IFN- production by Th1 cells. The IL-1
homologue, IL-1F7, also binds to IL-18BP and it has been proposed that it plays a role as a negative regulator of IL-18 activity.
When bound to IL-18BP, IL-1F7 can form a complex with
IL-18R chain preventing the formation of a functional receptor
complex [101].
IL-18: receptor and signalling
IL-18 signals through the IL-18 receptor complex (IL-18R),
which is a heterodimer consisting of IL-18R and -18R subunits.
The extracellular domains of both IL-18R chains contain three
Ig-like domains and an intracellular region comprising a Toll/IL-1
receptor (TIR) domain (Fig. 1). The IL-18R subunit is responsible for ligand binding, whereas the IL-18R subunit is a nonbinding signalling chain. The IL-18R complex is expressed on
lymphocytes and other cells such as plasmacytoid DCs [103] and is
up-regulated by IL-12, -2, [104, 105] and inhibited by IL-4 [106].
Following binding of IL-18 to the low-affinity IL-18R, the
IL-18R chain is recruited forming the high-affinity heterodimeric
receptor complex that brings the TIR domains within the intracellular regions of each receptor chain into close proximity. Once
the TIR domains of the IL-18R- and -chains are engaged
the adaptor protein myeloid differentiation factor 88 (MyD88)
then docks to the IL-18R complex resulting in the phosphorylation of IL-1 receptor-associated kinases (IRAKs) [107]. IRAK1
and IRAK4 have both been implicated in IL-18 signalling in NK
and Th1 cells, since IRAK1/, and in particular IRAK4/, mice
display impaired responses to IL-18 stimulation [108, 109]. IRAK
activation results in the recruitment of TRAF6. IB kinase (IKK)
is then activated and degrades IB, allowing NF-B to translocate
to the nucleus activating gene transcription [36].
IL-18 signal transduction is thought to be primarily mediated through this MyD88-dependent pathway. Indeed, MyD88 is
an essential component of IL-18R signalling, since Th1 cells from
MyD88/ mice are unresponsive to IL-18 [110]. In addition, the
inhibitory receptors Toll IL-1R 8/single Ig IL-1-related receptor
(TIR8/SIGIRR), which contain TIR domains in their intracellular
region, compete with the IL-18R complex for MyD88 and TRAF6
inhibiting IL-18 activity. Moreover, TIR8/SIGIRR-deficient mice
are more susceptible to IL-18 stimulation, whereas, cells overexpressing TIR8/SIGIRR are less susceptible to IL-18 stimulation
[111]. However, IL-18 has also been shown to induce the production of MCP-1 through the PI3K/AKT and MEK/ERK1/2
Role of Il-15 and -18 in autoimmunity
FIG. 3. Schematic representation of the functional activities of IL-18. IL-18 is
produced by many cell types including, macrophages, dendritic cells, oesteoblasts
and chondrocytes. In synergy with IL-12, IL-18 can induce the production of IFN-
by Th1 cells and NK cells, whereas it synergizes with IL-23, -18 to enhance IL-17
production by Th17 cells. IL-18 also enhances the production of pro-inflammatory
cytokines and chemokines by macrophages and synoviocytes. In basophils and
mast cells, IL-18, in the presence of IL-3, induces the production of IL-4 and -13,
which support Th2 responses. In B cells, IL-18 also induces the production of IL-4
and -13 and maintains IgE expression.
TABLE 2. The functional effects of IL-18 on cells of the immune system
Cell type
Th1 cells
Th17 cells
NK cells
B cells
Mast cells/Basophils
Functional Effects
In combination with IL-12, induces IFN- production
In combination with IL-23, enhances IL-17 production
Promotes functional development and cytotoxic activity
Enhances IL-4, IL-13 and IgE production
In combination with IL-3, induces IL-4 and IL-13 production
pathways. Inhibition of both of these pathways results in the
complete abrogation of IL-18-induced MCP-1 production
[112, 113].
A soluble form of IL-18R (sIL-18R) has recently been
identified, which is produced by differential splicing [114]. In vitro
studies reveal that the novel soluble receptor can inhibit IL-18induced IFN- production. A number of spliced variants of
sIL-18R have been identified. Indeed, it has been previously
observed that IL-18R exists as heterogenous molecules ranging
from 60 to 110 kDa [93]. It is therefore possible that IL-18Rspliced variants may each have distinct functions in the regulation
of IL-18 activity.
IL-18: biological activity
IL-18 acts synergistically with IL-12 to induce IFN- production
by several types of cells. IL-18 can induce IFN- production from
T cells independently of TCR activation, a property unique to
IL-18 [104] (Fig. 3 and Table 2). Considering the importance of
IFN- for pathogen clearance, IL-18 has been shown, using
animal models, to be required for the IFN--dependent eradication of several microbial infections. However, its biological role
extends beyond IFN- production and Th1 polarization. IL-18
induces both T- and NK-cell maturation and potentiates cytotoxicity. In fact, IL-18-deficient mice show reduced NK cytolytic
activity [113]. IL-18 is also involved in Th17 cell responses and,
in synergy with IL-23, can amplify IL-17 production by Th17polarized cells in a TCR-independent manner [115].
IL-18 can also induce TNF- production both in vitro and
in vivo, an effect that links this cytokine to the development
of the inflammatory response and the pathogenesis of several
autoimmune diseases. Chemokines such as CXCL8, CXCL5 and
CCL20 as well as adhesion molecule (ICAM-1, VCAM-1)
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expressions are also induced by IL-18 in isolated synovial tissue
fibroblasts and endothelial cells [116, 117].
On the other hand, IL-18 has been shown to have an indirect
role in inducing Th2 responses. IL-18 directly induces IL-4 and -13
secretion, as well as high IgE expression by B cells. The capacity of
IL-18 to induce a Th2 response depends on CD4þ T cells, NK-T
cells and IL-4. In fact, IL-18-induced IgE production is abrogated
in CD4þ T cell-depleted and in IL-4/ mice [118]. IL-18 can
induce the production of IL-4 and -13 even in the absence of
Fc"RI engagement if IL-3 is present in the milieu. Interestingly,
IL-12 and IFN- are incapable of blocking this IL-18-driven
activation suggesting that IL-18 involvement in the Th2 response
can occur in parallel with a Th1 response [119]. Along with
macrophages, IL-18 is also secreted by DCs, Langerhans cells,
osteoblasts and chondrocytes [120–122]. Moreover, IL-18
enhances the production of angiogenic and chemotactic factors
such as VEGF, CXCL12 and CCL2 in synovial fibroblasts [123].
Altogether, it is clear that, by regulating Th differentiation,
B-cell activation and Ig production as well as its activity on DCs,
NK and neutrophils, IL-18 is a cytokine that has an important
role in both the innate as well as the adaptive immune response
(Table 2).
IL-18: role in autoimmunity and allergy
Like IL-15, IL-18 exerts its effects on a wide array of cell types.
Consequently, this has implications for the pathogenicity of several
inflammatory diseases. Patients with Crohn’s disease have high
serum levels of IL-18 [124]. Accordingly, a correlation between the
level of IL-18 and severity of the disease has been shown in animal
models, whereas IL-18-deficient mice or mice treated with IL-18BP
can escape this disease. IL-18 also promotes the onset of insulindependent diabetes mellitus, through the Th1-mediated destruction of pancreatic -cells [125]. Transgenic expression of IL-18 in
murine keratinocytes results in the development of spontaneous
atopic dermatitis. Moreover, in several studies, patients have
shown a correlation between serum IL-18 and IgE levels and
severity of atopic dermatitis. A role for IL-18 has also been
postulated in bronchial asthma with elevated serum levels of IL-18,
which correlate with the severity of the disease [126]. In mice, IL-18
exacerbates airway inflammation and infiltration possibly
through the induction of chemokine release [126]. Increased
serum IL-18 levels have also been observed in allergic rhinitis
and, interestingly, a single nucleotide polymorphism in the IL18 gene has recently been associated with this disease [127, 128].
IL-18 has also been shown to be up-regulated in RA [129].
Elevated levels of IL-18 are found in the synovial tissue, synovial
fluid and sera of patients with RA. The administration of IL-18 to
mice with CIA significantly increases the severity of the disease
that is reduced following IL-18 blockade [130, 131].
Furthermore, the expression of IL-18 in rheumatoid synovium
has been found to correlate with IL-1 expression, macrophage
infiltration and inflammation. In addition, the bioactivity of
IL-18 from affected joints of patients with RA correlates with
disease severity. Notably, elevated IL-18BP levels have also been
described in RA [132].
Joint inflammation induced by IL-18 is partly TNF-
dependent. Mice deficient in TNF- display reduced lymphocyte
infiltration and joint inflammation in response to IL-18 [133].
Indeed, RA patients receiving the anti-TNF- antibody infliximab
show reduced IL-18 production and disease symptoms were
ameliorated [134]. As mentioned earlier, IL-18, in synergy with
IL-23, amplifies IL-17 production, which has been shown to play
a pathogenic role in autoimmune diseases, in particular RA, by
promoting cartilage destruction and osteoclastogenesis [135].
Targeting IL-18
Antagonizing the biological activity of pro-inflammatory cytokines such as IL-18 has the potential to improve symptoms and
1274
H. P. Carroll et al.
the pathological features associated with the inflammatory processes in which they are involved. To this end several therapeutic
approaches have been developed and are currently under investigation. The naturally occurring IL-18BP was first investigated as
a therapeutic approach in animals, with very promising results
[136–138] and is currently being tested in humans. As with all
naturally occurring inhibitors there are no problems related to
their possible immunogenicity; however, issues regarding their
pharmacokinetics still need to be addressed. From this point of
view, the use of mAbs specific for IL-18 and -18R may offer a
better solution. Indeed, animal models testing the efficacy of
mAbs against IL-18 and -18R have given results that warrant
further exploration in humans [139]. Considering the role of IL-18
in the normal immune response, it is possible that anti-IL-18
therapy may result in increased mycobacterial infections that have
previously been observed as a side-effect of anti-TNF therapy.
Furthermore, interfering with Th1 responses may alter the normal
anti-tumour immune response [140]. These and other possible
problems need to be taken into account in any therapeutic
approach directed towards IL-18 or its receptor.
IL-18 activity could be prevented by blocking caspase-1mediated cleavage of the cytokine into its mature form. This
approach would also prevent the formation of the mature form of
the pro-inflammatory cytokine IL-1. Agents capable of blocking
caspase-1 have already showed promising results in humans and
clinical trials are currently ongoing for the treatment of RA [141].
As mentioned earlier, the main downstream event in IL-18
signalling is the activation of NF-B. NF-B target genes are
involved in cellular events ranging from proliferation to inflammation and include genes for cytokines and chemokines as well as
cyclins and anti-apoptotic genes and it is through this transcription factor that IL-18 exerts its pro-inflammatory activity.
Historically, inhibition of NF-B has been found to be one of
the key mechanisms by which steroids, NSAIDs as well as some
natural and synthetic compounds act. Despite the prediction that
blocking NF-B may result in immunosuppression and increased
susceptibility to tumour development, several therapeutic strategies that target this pathway have been pursued. These include
inhibition of IkB phosphorylation and degradation as well as
inhibition of NF-B nuclear translocation. Compounds targeting
IKK molecules such as IMD-0560, SC-514, TPCA-1, BMS345541 and ML120B have shown promising activity in vitro and in
pre-clinical studies with block of the secretion and release of
metalloproteinase as well as cytokines and prevention of bone
erosion [142–146].
Among the drugs known to affect IB degradation, the boronic
acid peptide bortezomib, which has already been approved for the
treatment of human malignancies, is possibly the most interesting.
In pre-clinical studies in rats, bortezomib has been shown to
effectively reduce the severity of experimental autoimmune
encephalomyelitis (EAE) reducing the incidence of clinical
relapses, central nervous system (CNS) histopathology, and Tcell responses [147]. A plant-derived compound with a mechanism
of action similar to glucocorticoids has been recently described to
be able to block the inflammatory response [148]. This transrepression activity is also shared by some ligands of peroxisiome
proliferator-activated receptors (PPAR) and PPAR agonists have
shown efficacy in several pre-clinical models [110, 149–151].
Conclusions
In the past 15 yrs, our understanding of the complex cytokine
network, which is central to the pathogenesis of autoimmune
disease, is increased dramatically. In these two reviews, we have
aimed at highlighting the basic biology of a number of cytokines,
which we believe play a key role in the events that lead to chronic
inflammation and eventually, in the case of RA, articular inflammation and bone erosion. We have focused on the signalling
cascades and we have pointed out the therapeutic approaches that
are currently being developed to target such pathways. In the case
of IL-15 and especially IL-18, some of these approaches have
already moved from in vitro and pre-clinical studies to clinical
trials suggesting that this is indeed a way forward. It is now time
to move even further forward and an integration of the different
approaches, such as targeting multiple cytokines and multiple
pathways simultaneously, should result in greater therapeutic
efficacy with a reduction in side-effects as some of the in vitro and
in vivo work seems to suggest.
Rheumatology key messages
Among the complex network of pro-inflammatory cytokines
involved in the development of autoimmune diseases, IL-15
and -18 have both been shown to be of great importance.
The targeting of IL-15 and -18 for therapeutic purposes is already
a reality with a novel approach focussed on blocking their receptor
binding.
The intracellular pathways that these two cytokines activate
appear to be an exciting area of research, which may result in
novel drugs for the treatment of inflammatory diseases.
Disclosure statement: The authors have declared no conflicts of
interest.
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doi:10.1093/rheumatology/ken235
Advance Access publication 28 June 2008
Hypertrophic osteoarthropathy associated with a left
ventricular tumour
The patient, a 36-yr-old Polynesian man, presented with a
3-month history of swelling of his extremities with clubbing of
the fingers and toes and polyarthritis affecting his hands, feet and
knees. Plain radiographs revealed extensive periosteal reaction
along the shafts of the metacarpals (arrow in A). Axial proton
density fat saturated sequence on MRI shows periosteal new bone
(short arrow in B) involving the shafts of the metacarpals giving a
‘halo’ appearance. There is also associated periosteal oedema
showing high signal (long arrow). The patient was eventually
diagnosed with a high-grade undifferentiated pleomorphic sarcoma of his left ventricle (C, D). The hematoxylin and eosin
(H&E) section taken from the resected tumour (C) shows
pleomorphic spindle cell proliferation, bizarre nuclei and atypical
mitoses.
Vascular endothelial growth factor (VEGF), a cytokine
normally inactivated in the lungs, has been implicated in the
pathogenesis of hypertrophic osteoarthropathy [1].
Disclosure statement: The authors have declared no conflicts of
interest.
R. SUPPIAH1, F. MCQUEEN2
1
Department of Rheumatology, Auckland District Health Board,
Greenlane Clinical Centre and 2Department of Molecular Medicine
and Pathology, Faculty of Medicine and Health Sciences,
University of Auckland, Auckland, New Zealand
Accepted 28 May 2008
Correspondence to: R. Suppiah, Rheumatology Registrar,
Department of Rheumatology, Auckland District Health Board,
Greenlane Clinical Centre, Private Bag 92189, Auckland Mail
Centre, Auckland 1142, New Zealand.
E-mail: [email protected]
1 Olan F, Portela M, Navarro C et al. Circulating vascular endothelial growth factor
concentrations in a case of pulmonary hypertrophic osteoarthropathy. Correlation with
disease activity. J Rheumatol 2004;31:614–6.