DOI: 10.1002/eji.

201545780

Eur. J. Immunol. 2016. 0: 110

HIGHLIGHTS

Christian Schwartz 1 , Katie OGrady 2 , Ed C. Lavelle2

and Padraic G. Fallon1
1

School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2,
Ireland
2
Adjuvant Research Group, School of Biochemistry and Immunology, Trinity Biomedical
Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
Interleukin (IL)-33, a member of the IL-1 family, was originally described in 2005 as
a potent initiator of type 2 immunity found during allergic inflammation and parasitic
infections. IL-33 has been shown to play important and potent roles bridging innate and
adaptive immunity in the regulation of tissue homeostasis, injury, and repair. Recent
discoveries have extended the range of functions for IL-33 beyond type 2 conditions and
its role as an alarmin at barrier sites, with emerging central roles for IL-33 in T-cell
regulation, obesity, viral and tumor immunity. Here, we review the recent advances on
how IL-33 activity is regulated, its immunomodulatory properties on innate and adaptive
cells, and the newly discovered roles of IL-33 in obesity, intestinal inflammation, and
tumorigenesis.

Keywords: Cytokines r Immune regulation

Innate immunity r Interleukin-33

Introduction

IL-33expression and biochemistry

Interleukin (IL)-33 is commonly considered an alarmin released

upon cellular damage. IL-33 was originally discovered as a potent
driver of T helper type 2 (Th2) polarization [1]. Upon necrotic
release, IL-33 binds to the transmembrane isoform of the receptor ST2 (ST2L; also known as T1/ST2, IL1RL1, T1, Der4, Fit1,
or IL-33R), which is expressed on cells of the innate and adaptive immune system. In recent years it became evident that especially type 2 innate lymphoid cells are critical targets of IL-33.
Depending on other cells present in the microenvironment this
will shape adaptive immune responses and immunopathology.
This review will focus on recent advances in IL-33 regulation, cellular responses, and functions beyond the barrier alarmin function
in obesity, intestinal inflammation, and tumorigenesis.

Human and mouse Il33 both consist of seven coding exons, with
exons 13 coding for the N-terminal domain including the nuclear
localization sequence and a chromatin binding motif, and exons
47 coding for the C-terminal cytokine domain [2, 3]. The protein
consists of 270 (human) or 266 (mouse) amino acids and is stored
in the nucleus, but is able to act as a cell-free cytokine upon release.
Nuclear IL-33 can interact with histones and promote chromatin
compaction and can inhibit the transcriptional activity of NF-B
by binding to the p65 subunit of RelA [4]. The IL-1-like cytokine
domain of IL-33 folds into a 12-stranded -trefoil, which binds to
the ST2 receptor (ST2L) [5, 6].
Constitutive expression of IL-33 in humans and mice has been
observed in epithelial cells at barrier sites such as skin, lung, and

Correspondence: Padraic G. Fallon

e-mail: pfallon@tcd.ie


C 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

These authors contributed equally to this work.

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Review

Interleukin 33: an innate alarm for adaptive responses

beyond Th2 immunityemerging roles in obesity,
intestinal inflammation, and cancer

Christian Schwartz et al.

Eur. J. Immunol. 2016. 0: 110

Figure 1. Overview of IL-33-mediated inflammatory cascades from initial release from epithelial cells, adipocytes, or tumor stroma subjected to
insult or injury. IL-33 bioactivity is enhanced by proteases while beta-oxidation, caspases, its nuclear localization, and soluble ST2 (sST2) inhibit
IL-33 activity. Distinct ST2L+ innate cell targets such as basophils, ILC2s, and mast cells respond to IL-33 stimulation with the release of soluble
mediators (in red), which act on downstream targets alone or in combination with IL-33. Other factors that may contribute to IL-33-elicited
responses are shown in brackets. MC: mast cell, nILC2: natural type 2 innate lymphoid cell, TSLP: thymic stromal lymphopoietin, DC: dendritic
cell, NK: natural killer cell, CTL: cytotoxic T lymphocyte, Th: T helper cell, TREG : regulatory T cell, M: macrophage, B: B cell, PC: plasma cell, AREG:
amphiregulin.

intestine, and fibroblastic reticular cells within lymphoid tissues

[7], with IL-33 released from the nucleus through the destruction
of cellular integrity, which lead to its designation as an alarmin
[1, 79] (Fig. 1). During inflammatory responses, such as those
in allergic inflammation, IL-33 may also be actively released by
nonhematopoietic cells such as alveolar epithelial cells [10]. The
cell-bound receptor for extracellular IL-33, ST2L, consists of extracellular immunoglobulin-like domains and an intracellular TIR
domain. IL-33 binding to ST2L subsequently recruits the IL-1
receptor accessory protein (IL-1RAcP), which is necessary for signaling through MyD88, IRAK, IRAK4, and TRAF6 and downstream
activation of ERK1/2, p38, JNK, AP-1, and NF-B [1]. The biological activity of IL-33 is therefore mainly controlled by the expression
pattern of ST2L on target cells and the availability of IL-33 in the
environment.

Regulation of IL-33
Tight regulation of IL-33 expression prevents aberrant and lethal
inflammation [11]. Alternative splicing of the ST2 transcript
results in the expression of soluble ST2 (sST2) in the circulation,
which binds to IL-33, thereby inhibiting interaction with ST2L
[12] (Fig. 1). Transgenic overexpression of sST2 in the serum of


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mice directly inhibits IL-33 bioactivity upon systemic IL-33 administration [12]. The IL-1 receptor-like molecule SIGIRR has been
shown to act as a receptor antagonist for IL-33, interacting with
membrane-bound ST2L and thereby inhibiting ST2L signaling in
Th2 cells [13].
Unlike some other members of the IL-1 family, such as IL-1
and IL-18, full-length IL-33 released during necrosis is biologically
active and can be inactivated by caspase-1-mediated cleavage [8,
1416]. Using cell-free extracts of monocytic THP-1 cells, caspase3 and -7 have been shown to cleave and inactivate IL-33 within
the C-terminal domain in vitro [8, 1416] (Fig. 1). Thus caspasemediated processing of IL-33 provides a mechanism to regulate
IL-33-mediated pro-inflammatory responses.
Beyond caspase-mediated regulation, Cohen et al. [17]
recently described a novel mechanism for the rapid termination of
IL-33 bioactivity. An oxidation-driven conformational change in
the IL-33 molecule results in the formation of two disulfide
bonds between free cysteine side chains, generating a nonreduced, biologically inactive form of IL-33 [17]. Structural differences observed between the active and disulfate-bonded forms of
IL-33 were localized to the -barrel core as well as the top
-hairpin loop of the protein, sites that contain the high affinity ST2L binding site (Fig. 2) [17]. As a result of this conformational change, the disulfide-bonded form of IL-33 cannot induce

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Eur. J. Immunol. 2016. 0: 110

Figure 2. Structure of human and mouse IL-33. Blue areas highlight the location of cysteines, which form disulphide bridges and their oxidation
lead to conformational changes thereby abrogating binding to ST2L. This model was generated by SWISS-MODEL [95]. Protein accession numbers:
O95760, Q8BVZ5.

ST2L-dependent signaling. Using ELISAs to detect the reduced

and disulphide bonded/linked forms of IL-33 following Alternaria
challenge in wild-type and humanized mice, in vivo conversion by
beta-oxidation was shown to be rapid with the reduced bioactive form of IL-33 being undetectable 2 h after antigen challenge. In vitro exposure of human or mouse IL-33 to serum or
cell culture media substantiated these findings. Furthermore, an
IL-33 molecule with all four cysteines mutated demonstrated
intact ST2L-dependent signaling [17]. Therefore, SNPs in these
cysteines could predispose for exaggerated IL-33 bioactivity. The
identification of this conformational switch identifies a novel regulatory mechanism to limit the range and duration of IL-33 (and
notably also other IL-1 family members) activity.
While caspases and oxidation have both been shown to downregulate IL-33 activity, there is now compelling evidence that
the bioactivity of IL-33 can be amplified by extracellular proteases. The N-terminal domain of IL-33 is subject to proteolytic
processing, however, the targeted sequence within this domain
is protease-specific [18]. The neutrophil-derived proteases, elastase and cathepsin G, have been shown to process pro-IL-33 into
mature IL-33, resulting in a 10-30-fold increase in activity of
human IL-33 [18] (Fig. 1). Bronchoalveolar lavage fluid from mice
with neutrophil-dominated acute lung injury exhibited processed
IL-33, indicating a role for protease regulation during inflammation, although the relative contributions of the pro versus cleaved
forms of IL-33 in vivo remains a matter of debate [18] Interestingly, short-time co-incubation of IL-33 with the neutrophil serine
protease PR3 enhanced, whereas increased incubation time abrogated IL-33 bioactivity [19] (Fig. 1). Similarly, mast cell chymase
can also have enhancing or inhibiting effects on IL-33 activity.
Elevated airway and inflammatory responses to house dust mite
extracts were found in mast cell chymase-deficient mice, an effect
associated with a profound increase in IL-33 in lung tissue [20].


C 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Whether chymase directly degrades IL-33 [21] or matures IL-33 to

enhance ILC2 activation [22] remains unclear. Mast cells are not
only involved in the regulation of IL-33 activity, but are among
several other innate cell populations expressing ST2L that can be
activated by IL-33.

Innate roles for IL-33

Mast cells were shown to respond to IL-33 by maturation, degranulation, and the production of IL-6, IL-5, and IL-13, but also proinflammatory mediators such as cysteinyl leukotrienes, TNF-,
IFN-, IL-12, and IL-1 [23, 24] (Fig. 1). Flow cytometric analysis
revealed that mast cells may produce IL-33 in response to IgEmediated activation, accompanied by downregulation of ST2L,
directing IL-33 to other cell populations and thereby progressing
allergic inflammation [24]. Importantly, intracellular staining of
IL-33 for flow cytometry has not been validated in IL-33-knockout
mice and therefore expression of endogenous IL-33 in mast cells
warrants further investigation. Recently, it was reported that mast
cells upregulate MHC class II after prolonged IL-33 stimulation,
and thereby have the capacity to activate T cells in vitro [25].
In studies comparing Rag2/ mice, which cannot mount an
adaptive immune response, and Rag/ c / mice, which additionally lack ILCs, ILCs were identified as the main responders
to IL-33 [26]. Furthermore, ILC2s, which express high levels of
ST2L, release high concentrations of IL-5, IL-9, IL-13, and also
IL-4, GM-CSF, and amphiregulin following stimulation with IL-33
[27] (Fig. 1). IL-33-activated ILC2s can promote eosinophil expansion and survival, as well as the maintenance of M2-polarized
macrophages [28, 29]. Further roles for the IL-33-ILC2 interplay
were shown in IL-33-deficient mice, where IL-33 is required to
drive ILC2 production of IL-13, which is critical for the induction

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Christian Schwartz et al.

of goblet cell hyperplasia during Nippostrongylus brasiliensis infection [30]. Additionally, IL-33-activated ILC2s are required for IL-5
production and lung eosinophilia during Strongyloides venezuelensis infection and in a model of chitin-induced airway hyperreactivity [31, 32]. During influenza infection, IL-33 acts on lung
ILC2s to restore airway integrity by the release of amphiregulin
[34]. It has been further shown by flow cytometry that alveolar macrophages are the source for IL-33 [33], but the validation
of this assay is still pending. However, prolonged IL-33 release
during parainfluenza virus infection leads to abundant production of IL-13 by ILC2s, mucus overproduction, and chronic lung
inflammation [35]. After recruitment to the site of inflammation
through ILC2s, eosinophils respond to IL-33 by activating NF-B
and subsequently producing and releasing IL-4 and IL-13, as well
as prolonging cell survival [36, 37] (Fig. 1). This reinforced Th2cell polarization creates a feed-forward amplification of local type
2 inflammation [36, 37]. Furthermore, MHC class II expression
by IL-33-activated ILC2s and direct T-cell interactions promote
Th2 polarization [38]. Activated ILC2s have also been shown
to license DCs to produce CCL17, thereby recruiting eosinophils
and Th2 cells during memory responses [39] (Fig. 1). This suggests that early interactions between ST2L+ ILC2s, DCs, and Th2
cells shape the memory response against both pathogen-associated
and environmental antigens. Importantly, recent reports identified an IL-27 and IFN-mediated feedback mechanism counteracting IL-33-mediated activation of ILC2s, ultimately limiting type 2
immunopathology [40, 41].
Macrophages can respond to IL-33 by upregulating IL-13
mRNA, creating an autocrine M2 polarization loop and increasing
Th2 polarization in vivo [42] (Fig. 1). Furthermore, IL-33-induced
Arg-1 expression in bone marrow-derived macrophages (BMDM)
[43] and M2 macrophages has been shown to inhibit proliferation
of CD4+ T cells by enhanced expression of PD-L2 [44], ultimately
leading to an anti-inflammatory response by inhibiting T-cell proliferation through direct interaction and substrate competition.
Basophils also express ST2L and respond to IL-33 by producing GM-CSF, stimulating the expansion of dendritic cells [45]. In
addition, basophils are potent producers of IL-4 and IL-13, both
of which promote Th2 responses and may inhibit LPS-induced
activation of monocytes [46, 47] (Fig. 1).
DCs express high levels of intracellular ST2L. In vitro treatment of DCs with IL-33 leads to the production of IL-6 and the
upregulation of MHC class II and CD86, enhancing the capacity
of IL-33-stimulated DCs for Th2-cell polarization [48]. Pulmonary
exposure of mice to IL-33 leads to the recruitment of DCs to the
lung and their activation [49]. Interestingly, IL-33 can impose a
tolerogenic phenotype on DCs in the gut by inducing IL-2 release
from CD103+ CD11c+ DCs, leading to the expansion of regulatory
T (Treg) cells [50].
Taken together, a picture emerges in which IL-33 leads to the
predominant production of IL-5 and IL-13 from ILC2s at the site of
inflammation, causing eosinophil recruitment and survival, maturation of DCs, and alternative activation of macrophages. Channeling the innate IL-33-signal through ILC2s provides a platform for
shaping the adaptive immune response. Other cytokines present

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during the transient release of IL-33 may redirect early T-cell polarization (see Fig. 1).

IL-33 shaping adaptive immunity

Although IL-33ST2L interactions can clearly promote Th2 immunity and selectively induce IL-5 by ST2L+ memory Th2 cells [51],
it is now evident that other factors can act together with IL-33
to enhance Th1 responses. In particular, IL-33 in the presence of
IL-12 can induce IFN- production by iNKT and NK cells [52, 53].
IL-33-mediated ILC2 activation is required for Treg-cell accumulation under homeostasis or in inflamed tissue. Thus, IFN- inhibition of IL-33-mediated ILC2 activation also inhibits Treg-cell
expansion. The IFN--mediated diversion of the type-2 associated
IL-33-ILC2 pathway toward a pro-inflammatory state highlights
the potential to switch type-2 to type-1 responses [54]. Highly
activated effector Th1 cells have been shown to transiently express
ST2L during viral infection [55]. Lymphocytic choriomeningitis virus (LCMV)-induced Th1-cell activation is impaired in the
absence of ST2L, with expression of ST2L being dependent on the
transcription factors T-bet and STAT4. These results highlight the
context-specific role of IL-33 as a critical co-factor in driving Th1
effector cell responses [55].
IL-33, in parallel with the transcriptional regulators IRF4 and
BATF, can mediate the development and maintenance of adipose
tissue-resident Treg cells [56]. In vitro experiments have shown
that IL-33 acts together with IL-2 to promote the selective expansion of ST2L+ Treg cells [56]. Further experiments have shown
that DCs stimulated by IL-33 secreted IL-2, leading to the selective
expansion of suppressive ST2L+ CD4+ Foxp3+ regulatory T cells
(Fig. 1) [50]. This occurred in the absence of DC maturation [50].
Furthermore, IL-13R+ Th17 cells can be influenced indirectly by
IL-33 as targets of ILC2-derived IL-13, thereby decreasing IL-17Aproduction [57] (Fig. 1).
IL-33 can also act as a modulator of antigen-specific CD8+
T-cell responses. In mice, cytotoxic (CD8+ ) T cells were shown to
express high levels of ST2L, dependent on the transcription factor T-bet [58]. They further demonstrated that IL-33 synergized
with IL-12 to enhance IFN- secretion from effector CD8+ T cells
[58] (Fig. 1). Bonilla et al. [59] went on to demonstrate that the
IL-33-ST2L interaction on LCMV-activated CD8+ T cells is capable
of driving protective anti-viral CD8+ T-cell responses in mice. Villarreal et al. [60] further explored the adjuvant potential of IL-33
with a DNA vaccine, and showed that IL-33 enhances antigenspecific effector cells and effector memory CD8+ T-cell responses,
including enhanced IFN- secretion.
B1 cells can express ST2L and respond to IL-33 with proliferation and enhanced production of IgM, IL-5, and IL-13 [61].
B2 cells do not express ST2L, although one report describes an
unconventional regulatory B-cell population induced by IL-33 in
mice [62]. B-cell proliferation, differentiation, and class switch to
the type-2-associated isotypes IgG1 and IgE is induced by IL-4,
IL-5, and IL-13 [6365], cytokines produced by IL-33-activated
innate cells, such as ILC2s, eosinophils, and basophils. IL-33 thus
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HIGHLIGHTS

Figure 3. Overview of IL-33-mediated effects in obesity, intestinal inflammation, and tumorigenesis. Obesity is associated with pro-inflammatory
responses. IL-33 released from endothelial cells and adipocytes leads to the recruitment of anti-inflammatory cells and promotes conversion to
energy-burning fat. Damage of the intestinal epithelia releases IL-33, which acts on ILC2s, mast cells, and promotes the upregulation of ST2L
on Treg cells rendering them IL-33-responsive. The release of amphiregulin and type 2 cytokines promotes wound healing. IL-33 can directly
promote epithelial cell transformation or indirectly lead to a microenvironment beneficial for tumor growth. However, IL-33 can also increase the
anti-tumor response by cytotoxic T cells (CTL) and NK cells.

has both direct and indirect impact on B-cell proliferation and

function.
The concerted action of innate and adaptive immune cells in
response to IL-33 leads to the development of appropriate immune
responses, however, dysregulation of this controlled network promotes immunopathology. Some aspects of this dysregulation and
its consequences in obesity, gut inflammation, and tumorigenesis
are discussed below.

Disease-specific functions of IL-33

An extensive body of work from the past decade has established the central role of IL-33 in helminth infections, hepatic
and pulmonary fibrosis, allergic airway inflammation, rheumatoid
arthritis and multiple sclerosis (reviewed in [66]). In this article
we will address recent studies ascribing new functions to IL-33
during obesity, intestinal homeostasis and cancer development
(Fig. 3).

IL-33 and obesity

Obesity is associated with an unresolved low-level proinflammatory state and the presence of Th1 cells, CD8+ T cells,


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and M1 macrophages within the adipose tissue. Conversely, the

fat of lean individuals is populated with anti-inflammatory M2
macrophages, ILC2s, eosinophils, and Treg cells (reviewed in
[67]). In mice, abundant IL-33 has been shown to regulate white
adipose tissue homeostasis via ST2L+ ILC2s and Treg cells [29].
When this process is dysregulated, a proinflammatory response
develops, leading to obesity, insulin resistance (IR), and metabolic
syndrome [29]. In a recent report, it was shown that the helminthderived RNase 1 induces IL-33 release from adipocytes from
obese mice and also in man [68], which have previously been
shown to express IL-33 [69]. Additionally, it has been shown that
abundant IL-33 is expressed in adipose tissue endothelial cells [54]
(Fig. 3). Due to different detection methods it remains unclear
whether adipocytes constitute a significant source of IL-33 in vivo
and further investigation is required. Subsequently, release of type
2 cytokines, such as IL-4, IL-5, and IL-13, and local accumulation of
ILC2s, Th2 cells, eosinophils, and M2 macrophages within the adipose tissue lead to ILC2-dependent weight loss in mice [68, 70].
These observations are in line with earlier reports showing an
important role for eosinophils and M2-polarized macrophages
in the homeostasis of visceral adipose tissue [71]. Furthermore,
ST2L+ Treg cells are diminished in obese mice, which can be
restored by IL-33 administration [72]. Interestingly, Treg cells
upregulate GATA3 upon IL-33 treatment, and GATA3, which can
be induced through STAT6-signaling, has been shown to regulate

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Christian Schwartz et al.

Treg-cell fate and expression of ST2L [73, 74], indicating another

primary target of IL-33. In contrast to the obesity-induced IR, an
age-related IR was shown to be promoted by fat-resident ST2L+
Treg cells [75]. However, the contribution of ST2L+ ILC2s in this
process was not analyzed. White adipose tissue can be converted
into brown adipose tissue (thermogenesis) by IL-33 and IL-25
acting on ILC2s [76, 77]. This process is naturally initiated by
cold-induced genes, with their expression shown to be dependent
on eosinophils and type 2 cytokines [78]. Furthermore, upregulation of Ucp1 in adipocytes and commitment to the brown fat
lineage can be induced by ILC2-secreted methionine-enkephalin
peptides [76] (Fig. 3). Most recently, it has been revealed that
it was indeed IL-33-activated ILC2s that regulated this process
by stimulating PDGFR+ adipocyte precursors to commit to the
brown fat lineage via IL-4R-dependent signals [70]. In summary,
IL-33 released from adipocytes or adipose tissue endothelial cells
promotes the amelioration of obesity by acting on ST2L+ ILC2s.
This generates an anti-inflammatory milieu accompanied by accumulation of ST2L+ Treg cells, M2 macrophages, and eosinophils
and the conversion of energy-storing into energy-consuming fat
(Fig. 3).

IL-33 and intestinal inflammation

The intestinal microenvironment is characterized by constant
encounter with microbial antigens. The equilibrium between
inflammation and tolerance toward the microbial flora can easily tip out of balance. In this context IL-33 is released during
epithelial cell damage and initiates the subsequent innate response
to activate barrier restoration, but also induces anti-helminthic
responses. Earlier studies using a DSS-colitis model showed that
exogenous IL-33 could divert the Th1-type response toward a Th2type response [79], yet recent studies suggest that Treg cells
present in the colon selectively upregulate ST2L+ in response
to tissue damage and restrain local inflammation [80] (Fig. 3).
IL-33 has been shown to promote Treg-cell function by enhancing TGF-1-mediated differentiation and by providing a signal
for Treg-cell accumulation and maintenance in the intestine in a
murine model of acute colitis [80]. Importantly, in this study,
IL-23 served to restrain Treg-cell responses through inhibition
of IL-33 responsiveness [80]. Whether IL-33-induced Treg-cellderived amphiregulin plays a critical role in tissue repair in the
gut, as has been shown during airway remodeling [81], remains
to be determined. Another study provided evidence that during
epithelial damage in the intestine, IL-33-activated ILC2s and mast
cells release amphiregulin to restore barrier integrity by acting on
EGF-responsive cells [82], such as Treg cells [83]. Thus it seems
probable that IL-33 activates ILCs and Treg cells, with both potentially increasing amphiregulin release (Fig. 3). Together with type
2 cytokine release by ILC2s, this creates an anti-inflammatory environment opposing TLR-ligand-induced inflammation and promoting tissue repair.


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IL-33 and tumorigenesis

Increasing evidence now points to IL-33 as a possible inducer
and prognostic marker of cancer development. In a mouse model
of colorectal cancer, IL-33 was shown to be induced in adenomatous cells and to activate ST2L+ mast cells and subepithelial
myofibroblasts; these activated cell types in turn release proangiogenic and growth factors, thereby promoting a tumorigenic environment and polyposis [84] (Fig. 3). A recent study showed that
IL-33 signaling contributes to the development of myeloproliferative neoplasms (MPN) [85]. Genetic ablation of IL-33-signaling, in
particular in radioresistant cells, abrogated MPN in SHIP-deficient
animals, which normally develop this disease [85]. In this model,
IL-33 was released by stromal cells in the bone marrow, with
increased levels of IL-33-expressing cells found in bone marrow
samples of MPN patients. In line with these findings, IL-33 has
also been shown to promote human epithelial cell transformation
in vitro and knockdown of IL-33 or ST2L in breast cancer cells
decreases their tumorigenesis [86]. In a mouse model of breast
cancer, IL-33 administration promoted increased cancer cell survival and metastasis [87]. Furthermore, human gastric cancer cells
show increased invasive and migratory capacity in vitro following
IL-33 treatment [88]. Taken together, these studies suggest that
the IL-33/ST2L axis may initiate cancer development and promote
metastasis. Emerging evidence suggests that IL-33 may serve as a
prognostic marker during ovarian and lung cancer and also squamous cell carcinoma [8991]. Interestingly, tumor-derived IL-33
may also inhibit tumor growth by increasing the number of infiltrating NK cells and CD8+ T cells [92], and IL-33-activated NK
cells further contributing to anti-tumor immunity [93] (Fig. 3).
Further experiments are needed in order to clarify the role of
IL-33 during cancer development and whether tumorigenesis can
be influenced by other cytokines inhibiting IL-33-mediated effects.
In these scenarios, IL-33 triggers NF-B-activation, which may
lead to neoplasms, and furthermore, IL-33 is exploited by established tumor cells to create a favorable environment by inducing
a Th2/anti-inflammatory environment.

Conclusion
This review highlights the potency of IL-33 and the remarkable
span and diversity of its immunomodulatory effects in health and
disease (Fig. 3). Taken together, IL-33 mainly exerts its functions
through the timely activation of cells present at the site of tissue injury. Activated ST2L+ cells such as ILC2s and mast cells
release cytokines and recruit eosinophils and macrophages to the
site of inflammation. The automatic inactivation of IL-33 by oxidation during the first few hours after the insult highlights the
requirement to tightly regulate its activity to prevent an uncontrolled inflammatory cascade. Rather than acting in isolation,
the cytokine milieu will shape the developing adaptive immune
response (Fig. 1). Sustained IL-33 expression, however, will act
on ST2L+ T cells and promote type 2-driven immunopathology.

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Interestingly, new roles of IL-33 have now been described during

obesity, intestinal inflammation, and cancer development. Indeed
this highlights that initial IL-33 release can instruct innate immune
cells to direct the outcome of an adaptive immune responses that
can impact on chronic inflammatory diseases.
Because of its potency and central role in tissue-damageinduced inflammation and tumorigenesis, IL-33 is a promising
target for therapeutic intervention. Different approaches could be
envisioned. The use of IL-33 as an adjuvant has been considered
as a means to drive Th2 polarization [94], but caution should be
exercised given the many target cell populations and the potential
for driving tumor progression. A biologics approach using neutralizing antibodies directed against IL-33 or ST2L could be used
to limit the bioactivity of IL-33. However, their use may be limited due to the oxidation of cysteine residues and the presence of
short-acting IL-33 within tissue microenvironments. In this context, beta-oxidation may have led to an underestimation of IL-33
levels in various inflammatory settings due to an inability to measure IL-33 before degradation. Targeting neutrophil elastase or
mast cell chymase could alleviate IL-33-mediated inflammation;
however, this could lead to suppression of other cytokines required
for host defense against invading pathogens. A deeper understanding of microenvironmental influences on the immunomodulatory
effects of IL-33 is required to allow targeted therapeutic manipulation of the cytokine.

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Acknowledgments: P.F. is supported by Science Foundation

Ireland (SFI) and National Childrens Research Centre. E.L. is
supported by SFI under Grant number 12/IA/1421 and the
SFI Research Centre, Advanced Materials and BioEngineering
Research (AMBER) under Grant number SFI/12/RC/2278.

molecule/Toll IL-1R8 in regulation of Th2 immune response. J. Immunol.

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Conflict of interest: The authors declare no financial or commercial conflict of interest.

16 Luthi, A. U., Cullen, S. P., McNeela, E. A., Duriez, P. J., Afonina, I. S.,
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C 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Received: 4/12/2015
Revised: 20/2/2016
Accepted: 15/3/2016
Accepted article online: 22/3/2016

www.eji-journal.eu