Cytokine & Growth Factor Reviews 26 (2015) 579–586

Contents lists available at ScienceDirect

Cytokine & Growth Factor Reviews

journal homepage: www.elsevier.com/locate/cytogfr

Mini review

The biology of interleukin-27 reveals unique

pro- and anti-inflammatory functions in immunity
Samadhi Aparicio-Siegmund, Christoph Garbers *
Institute of Biochemistry, Kiel University, Olshausenstrasse 40, Kiel 24098, Germany

A R T I C L E I N F O A B S T R A C T

Article history: Interleukin (IL)-27 is a multifaceted heterodimeric cytokine with pronounced pro- and anti-
Received 5 June 2015 inflammatory as well as immunoregulatory functions. It consists of the two subunits p28/IL-30 and
Accepted 1 July 2015 Epstein Bar virus-induced protein 3 (EBI3). EBI3 functions as a soluble a-receptor, and IL-27 can
Available online 3 July 2015
therefore directly activate its target cells through a heterodimer of glycoprotein 130 (gp130) and WSX-1.
Being a heterodimeric cytokine that signals through gp130, IL-27 is either grouped into the IL-6 or the
Keywords: IL-12 family of cytokines. Originally identified as an IL-12-like cytokine that induces proliferation of
Interleukin-27
CD4+ T cells and production of IFN-g more than ten years ago, subsequent research revealed a much
EBI3
p28
broader role of IL-27 in inflammation, cancer development and regulation and differentiation of immune
gp130 cells. In this review, we summarize the current biochemical and molecular knowledge about the signal
WSX-1 transduction of IL-27. Based on this, we highlight functional overlaps and plasticity with other cytokines
and cytokine receptors of the IL-6/IL-12 superfamily, and describe the important role of IL-27 with
regard to the differentiation of T cells, infections and cancer development. We further discuss IL-27 as a
therapeutic target and how specific blockade of this cytokine could be achieved.
ß 2015 Elsevier Ltd. All rights reserved.

1. Introduction response to a parasitic infection revealing a non-redundant

Interleukin-27 (IL-27) is a heterodimeric cytokine that because
of structural properties and shared receptors belongs to the IL-6/IL-
12 superfamily of cytokines. It is composed by the two subunits
p28 (IL-27a, IL-30) and EBI3 (Epstein-barr virus-induced gene 3, IL-
27b) [1]. The a-subunit p28 is a four-helical bundle cytokine like
the other members of the IL-6-family, and EBI3 is the soluble a-
receptor that consists of two fibronectin-like domains [2] (Fig. 1).
The receptor complex that transduces the signal of IL-27 is
composed of gp130 and WSX-1 which form a heterodimer on the
cell surface that activates predominantly the Jak/STAT pathway
but also PI3K/Akt and MAPK signaling (Fig. 1). In contrast to the
pro-inflammatory actions of IL-6 through gp130, IL-27 was initially
described to have immunoregulatory functions. This was based on
the finding that IL-27 induces the secretion of IL-10 and limits
inflammatory responses in the context of infection. Although IL-27
is an inducer of IFN-g expression, which is part of its pro-
inflammatory actions, lack of WSX-1 in mice does not alter IFN-
g-mediated immunity, but induces an immune hyperactivity in
immunoregulatory function of IL-27 [3] (see Section 5). Together
with IL-12, IL-27 can promote the IFN-g-induced Th1 response and
on the other hand it induces IL-10 producing, forkhead box
transcription factor p3-positive (Foxp3+) regulatory T cells (Tr1
cells), limits IL-2 production and reverses the IL-23 mediated
lineage commitment of Th17 cells [4–7] (see Section 4). These
unique properties show that categorizing this cytokine as pro- or
anti-inflammatory is rather simplistic and does not cope with the
complex interactions in the cytokine network.
Because of the nature of the heterodimer it is not trivial to
discriminate between IL-27 related or independent functions of
the two subunits. The soluble a-receptor EBI3 can also bind p35
and have agonistic functions as IL-35 and p28 is known to be
secreted in the absence of EBI3 in complex with CLF-1 and to exert
functions through binding to the IL-6R [8–10].
Thus, we dissect the biology of IL-27 and its individual subunits
in terms of inflammation, infection and cancer, and discuss
opportunities and potential pitfalls when studying IL-27 in vivo.
2. Expression of interleukin-27 and its receptors

* Corresponding author. Tel.: +49 431 880 1676; fax: +49 431 880 5007. Although p28 is poorly secreted when expressed in the absence
E-mail address: cgarbers@biochem.uni-kiel.de (C. Garbers). of EBI3, the transcription of both subunits is independently

http://dx.doi.org/10.1016/j.cytogfr.2015.07.008
1359-6101/ß 2015 Elsevier Ltd. All rights reserved.
580 S. Aparicio-Siegmund, C. Garbers / Cytokine & Growth Factor Reviews 26 (2015) 579–586
Fig. 1. Interleukin-27 and its receptor complex. IL-27 is composed of the subunits p28
and EBI3 and induces the formation of the receptor complex consisting of gp130
and WSX-1. These b-receptor chains are associated with Janus kinases (Jaks) that
upon activation phosphorylate the cytoplasmic tyrosine residues of the b-receptors
and the associating STAT transcription factors. Ex: extracellular space, Cyt: cytosol.
regulated. In humans IL27A is located on chromosome 16 whereas
IL27B is located on chromosome 19.
The primary source of p28 and EBI3 are cells of the myeloid
lineage mainly monocytes and activated dendritic cell [1]. The
IL-27p28 mRNA is not detectable under steady state conditions,
but is upregulated in murine splenocytes after infection [3].
Recently, it was shown that especially plasmacytoid dendritic cells
(pDCs) from the liver express detectable amounts of mRNA for
IL-27p28 without infection and that the protein levels are higher
than in pDCs from the spleen. Also here it was shown that the
expression levels of the subunit p28 are strongly regulated
whereas transcript and protein levels of EBI3 are comparable
and constitutively present in various cell types [11].
LPS-induced endotoxic shock in mice strongly increases p28
levels, which originate mainly from macrophages residing in the
spleen and to a lesser extent in the lung. This elevated expression is
reversed by IL-10 in a STAT3-dependent manner, revealing a
negative feedback mechanism for IL-27 induced IL-10 production
[12]. Furthermore, upregulation of both EBI3 as well as p28 occur
during T cell activation with low but detectable levels in both naı̈ve
and memory CD4+ T cells and also in B cells [13].
The receptor complex for IL-27 consists of the two subunits
gp130, which is ubiquitiously expressed and the main signal
transducing b-receptor of the IL-6 family, and WSX-1, which has
Fig. 2. Plasticity among IL-6, IL-27 and IL-35. IL-35 (p35/EBI3) has been described to signal via the four different b-receptor complexes gp130/gp130, IL-12Rb2/gp130, IL-
12Rb2/IL-12Rb2 and IL-12Rb2/WSX-1. IL-27 (p28/EBI3) signals via gp130/WSX-1, whereas p28/sIL-6R and IL-6/sIL-6R induce formation of a gp130/gp130 homodimer.
Soluble gp130 (sgp130) blocks signaling of IL-6/sIL-6R and p28/sIL-6R, but not IL-27. Soluble WSX-1 (sWSX-1) inhibits IL-27 signaling, but not IL-6/sIL-6R and p28/sIL-6R.
Whether sgp130 or sWSX-1 interfere with IL-35 signaling is not known. Ex: extracellular space, Cyt: cytosol.
few known functions apart from IL-27 signaling. As gp130, WSX-1
is a type I transmembrane protein that activates the Jak/STAT
signaling pathway upon ligand binding and receptor complex
formation. WSX-1 is expressed in low levels on naı̈ve and higher
levels on effector and memory T cells which renders them the main
targets of IL-27 actions [14].
Apart from this canonical receptor complex both cytokine
subunits are also described to activate other receptors. Cross-talk
between the actions of the many cytokines takes place on various
levels. Through different subunit pairing especially in the IL-12
family EBI3 as well as p28 are used by different cytokines. EBI3 can
form the cytokine IL-35 by binding the IL-12 subunit p35 [15,16],
although the interaction site seems to be very unconventional
in the context of this cytokine family [17]. For p28 it was shown
that the site II binding to the cytokine binding module (CBM) of
different cytokine b-receptors is depending on the bound
a-receptor, in this case EBI3 or the IL-6R, which results in the
activation of a gp130/WSX-1 heterodimer by IL-27 and the
activation of a gp130 homodimer by p28 through the IL-6R [10].
All these data suggest that the binding surfaces of the subunits and
the receptors reveal a high plasticity and depend on the different
interaction partners and complexes in which the cytokines occur
(reviewed in [18], Fig. 2).
3. Signal transduction and cross-talk of IL-27
The main signal transducing receptor of the IL-6 family of
cytokines is gp130, which is constitutively interacting with kinases
of the Janus family namely, Jak1, Jak2 and Tyk2. Concerning the
signaling of IL-6-type cytokines only Jak1 has non-redundant
functions and loss of Jak1 cannot be compensated by the other two
kinases [19,20]. WSX-1 appears to have the same box 1 motif that
mediates the interaction with the Jak kinases in the cytoplasmic
portion of the receptor. Ligand binding and receptor complex
formation lead to mutual activation of the associated Jaks and
subsequent phosphorylation of intracellular tyrosine residues of
gp130 and WSX-1 [21]. STAT proteins are then recruited to the
phosphorylated receptor and likewise activated by the Janus
Kinases through phosphorylation to induce their target genes.
In contrast to the other IL-6-type cytokines IL-27 induces a
stronger phosphorylation of STAT1 but also the activation of other
STATs like STAT3 and STAT6 [22,23]. The STAT binding site in the
cytoplasmic region around Tyr613 of hWSX-1 is specific for the
binding of STAT1. The conserved binding motif GYEKHF is closely
 S. Aparicio-Siegmund, C. Garbers / Cytokine & Growth Factor Reviews 26 (2015) 579–586
related to the one in the IFN-gR (GYDKPH) which activates tyrosine
phosphorylation of STAT1 in a selective manner [24].
Apart from STAT activation IL-27 also leads to the activation of
ERK, p38 MAPK and Akt signaling, which could be shown in
intestinal epithelial and liver cell lines [19,23]. In DLD-1 cells
inhibition of p38 MAPK lead to reduced IL-27-induced prolifera-
tion. ERK activation as well as p38 signaling are necessary for Th1
differentiation and IL-12Rb2 upregulation mediated by IL-27
[23,25].
The most important negative regulator of gp130/Jak/STAT
signaling is SOCS3. STAT3 induces the expression of this protein
that binds to gp130 and the Janus kinases and inhibits them
by binding directly to their kinase domain. Subsequently SOCS3
leads to degradation of both the receptor complex and the
associated Janus kinases by recruiting an E3-Ubiquitin-Ligase
complex [26,27]. IL-27 induces SOCS3 although it seems that its
expression is dispensable for at least some functions of IL-27 like
antagonizing Th17 lineage commitment [7].
The actions of the diverse gp130 binding cytokines cumulate in
the very same signal transduction pathways and all IL-6-type
cytokines induce a STAT3 phosphorylation, which cannot be
compensated by other STATs. It is still a major goal to identify the
mechanisms that mediate the specificity of those cytokines that
have common, but also unique target genes.
SOCS3 seems to be one of the players that guide different
outcomes of similar signaling pathways. IL-6 and IL-10 induce very
opposed impacts with IL-6 being rather pro-inflammatory and
IL-10 having anti-inflammatory effects. Both activate STAT3
through their receptors which induce SOCS3 expression but only
IL-6 signaling is altered by this inhibitory molecule as it interacts
with phospho-Tyr759 of gp130 but not with phosphorylated
tyrosine residues in the IL-10R. Surprisingly, when macrophages
that are stimulated with LPS and IL-6 lack of SOCS3 or its binding
site in gp130 their response is rather anti-inflammatory similar to
their response to IL-10 meaning that IL-10 modulates the response
to IL-6-type cytokines by inducing SOCS3 [28,29]. On the other
hand, IL-27 induces the expression of SOCS3 via STAT3, although it
has been described to have opposing functions to IL-6.
The other factor that has recently been identified as a
specificity conferring factor is STAT1. Hirahara et al. showed
that IL-27 is not just a strong STAT1 inducer but needs STAT3 for
its functions. Both IL-27 and IL-6 lose more than 75% of their
target genes when STAT3 is missing. Surprisingly lack of STAT1
has a totally different impact in murine CD4+ activated T cells in
their study. It leads to a drastic increase in commonly regulated
genes by those two cytokines meaning that this transcription
factor confers the differences in gene induction between the two
cytokines [30]. These and other data show that for example
priming of cells with IFN-g or gain of function mutations in STAT1
would result in an altered IL-27 response and increased
distinction compared to an IL-6 response [31].
Differences in the impact of the cytokines might be contributed
by many different factors like availability of cytokine subunits,
receptors and transcription factors and cross-talk with other
cytokines and growth factors in each microenvironment and it still
remains a major goal to find approaches that contribute to the
understanding of this complex network.
4. Role of IL-27 in the differentiation of T cells
IL-27 has a profound role in controlling the differentiation of
several T cell subsets, which is crucial in vivo during infection (see
Section 5). Already the initial report that identified IL-27 as a
functional cytokine showed that IL-27 induced proliferation of
human and murine naı̈ve CD4+ T cells, but not memory T cells [1].
They could further show that IL-27 acted in concert with IL-12, and
581
that both cytokines synergistically induced production of IFN-g by
human and murine naı̈ve T cells [1]. Mechanistically, IL-27 induced
expression of the Th1-specific transcription factor T-bet, and
suppressed expression of GATA-3, which is a Th2 specific
transcription factor [22]. T-bet drives expression of IL-12Rb2,
which together with IL-12Rb1 constitutes the signal-transducing
b-receptors for IL-12, and their expression level determines the
responsiveness of cells towards IL-12. Impaired IL-12-dependent
IFN-g production was further shown in WSX-1 / naı̈ve CD4+
T cells [32]. Thus, IL-27 plays an important role in Th1
differentiation by controlling the IL-12 responsiveness in a
paracrine manner [22]. Accordingly, patients with chronic immune
thrombocytopenia show increased serum levels of IL-27 and
increased Th1 cell numbers [33].
Besides IL-12Rb2, IL-27 also controls the expression of several
other receptors on CD4+ T cells, e. g. the receptor activator of NF-kB
ligand (RANKL), which underlines the role of IL-27 in bone
destruction [34,35]. IL-27 has also been shown to be critically
involved in the control of expression of the pro-inflammatory
cytokine granulocyte macrophage colony-stimulating factor (GM-
CSF) [36]. In CD4+ and CD8+ T cells, IL-27 suppressed GM-CSF
expression, which was independent of IL-2, IL-10 or SOCS3. Whereas
expression of RANKL was dependent on STAT3 signaling, the control
of GM-CSF expression by IL-27 was dependent on STAT1 [34,36].
Stimulation of CD4+ T cells with IL-23 leads to the production of
IL-17, and this distinct T cell subset has been termed Th17 cells
[37]. However, later reports showed that transforming growth
factor-b (TGF-b) in combination with IL-6 was a potent inducer of
Th17 cells [38,39], and that IL-6 trans-signaling via the soluble IL-
6R plays a pivotal role in Th17 maintenance [40]. However, IL-6-
dependent and -independent pathways in the development of
Th17 cells have been described [41].
IL-27 inhibited Th17 cell development of naı̈ve T cells in
response to TGF-b and IL-6 [7]. This suppression was dependent on
STAT1, but independent of SOCS3 [7]. Mechanistically, IL-27
blocked in a STAT1-dependent manner the expression of RORgt,
which is a Th17-specific transcription factor that drives the
expression of IL-17A and IL-17F in both human and murine T cells
[42]. Another mechanism that counteracts Th17 development is
the upregulation of programmed death ligand 1 (PD-L1) by IL-27
on naı̈ve T cells. These primed T cells inhibited Th17 differentiation
in trans through a PD-1-PD-L1 interaction [43]. IL-27 has nearly no
effect on already developed Th17 cells, although these cells express
WSX-1 and gp130 [44]. Besides this activity on Th17 cells, IL-27
was also able to suppress the development of Foxp3+ anti-
inflammatory, inducible regulatory T cells (iTregs) [45]. In contrast
to the blockade of Th17 development, the suppression of iTregs
was independent of STAT1, underlining that IL-27 can induce
signaling in T cells via different pathways [45].
Another important T cell subset that is influenced by IL-27 are
the so-called Tr-1 cells, which are Foxp3– regulatory CD4+ T cells.
IL-27 is a potent inducer of IL-10 production in these cells, and Tr-1
cells are considered the major source of IL-10 during inflammation
[46,47]. IL-10 is a major anti-inflammatory cytokine, which
coordinately dampens the immune response at several stages
during infection [48]. The mechanism behind IL-27’s ability to
induce IL-10 production has been shown to consist of expression of
the transcription factor c-Maf, IL-21, and the costimulatory
receptor ICOS [49]. IL-27 induces IL-21 expression through
c-Maf, and IL-21 leads to expansion and maintenance of Tr-1
cells in an autocrine fashion, whereas ICOS promotes Tr-1 cells
induced by IL-27. Depletion of one of the three factors is sufficient
to reduce IL-10-producing Tr-1 cells [49]. However, the mecha-
nism behind IL-10 production by Tr-1 cells appears to be even
more complex. A recent report showed that Th17 cells upregulated
the transcriptional regulator Blimp1 in response to IL-27 and IL-12
582 S. Aparicio-Siegmund, C. Garbers / Cytokine & Growth Factor Reviews 26 (2015) 579–586
and adopted a Tr-1-like phenotype [50]. These Tr-1-like cells
produced IL-10 and IFN-g. Interestingly, IL-23 was able to reverse
the phenotype and to re-induce pro-inflammatory Th17-like
properties, thus counteracting IL-12 and IL-27 and suggesting
that a balance between IL-23 on the one hand and IL-27/IL-12 on
the other hand regulates CD4+ differentiation [50].
5. Role of IL-27 during infection and inflammation
IL-27 has a profound anti-inflammatory and well characterized
role in the control of infections due to its ability to modulate T cell
responses and T cell differentiation (see Section 4). For example,
IL-27 induces proliferation of CD4+ T cells and their differentiation
into Th1 cells. To study the role of IL-27 in Th1 generation in vivo,
Yoshida et al. generated WSX-1 / mice and infected them with
Leishmania major [51]. The mice showed increased susceptibility
towards the infection together with impaired production of IFN-g
in the early stages. However, IFN-g production was normal in the
late phase of the infection, and the authors concluded that IL-27
signaling via WSX-1 was important for the initial Th1 response, but
not for their maintenance [51]. The altered production of IFN-g in
response to L. major infection in WSX-1 / mice was confirmed
independently; however, in this study the authors reported that
the knock-out mice successfully controlled replication of the
parasites [52]. In contrast to L. major infection, WSX-1 / mice were
more resistant to infection with L. donovani and were able to
control parasite growth faster than wildtype animals, although
they developed a severe liver pathology [53].
Moreover, WSX-1 / mice infected with Toxoplasma gondii
elicited a strong production of IFN-g that was accompanied with a
protective T cell response and control of parasite replication [3].
However, the animals died at later timepoints suffering from T cell-
mediated inflammatory disease. Overproduction of IFN-g in WSX-
1 / mice was further shown in an infection model with the
intracellular parasite T. cruzi, which causes Chagas’ disease in
humans [54]. WSX-1 / mice displayed enhanced parasitemia in
combination with necrotic lesions of the liver and increased
mortality [54]. Further evidence for an important role of IL-27 in
the induction of Th1 responses came from a study where WSX-1 /
mice were infected with gastrointestinal nematode Trichuris muris.
In contrast to wildtype mice, WSX-1 / mice had a reduced Th1
response and an unaltered Th2 response [55]. In sharp contrast, a
different group with the same helminth parasite and the same
knock-out mice found increased production of Th2 type cytokines,
increased expulsion of parasites, mastocytosis and goblet cell
hyperplasia [56]. Although these studies reported conflicting data,
it is obvious that the action of IL-27 in vivo is not restricted to the
polarization of Th1 cells. Rather, IL-27 acts as an anti-inflammatory
cytokine that has the ability to control Th1 and Th2 responses
during several types of infections. However, due to the fact that IL-
35 can also signal via WSX-1 (Fig. 2), one has to be careful when
interpreting results achieved with WSX-1 / mice.
The influence of IL-27 on the development of Th17 cells during
infection is much clearer. Chronic infection of WSX-1 / mice with
T. gondii led to a CD4+ T cell-dependent neuroinflammation,
enhanced numbers of Th17 cells in the brain, and an increase in
IL-17 production [7]. Likewise, WSX-1 / mice were more suscepti-
ble towards EAE, the murine model of multiple sclerosis, and
generated more Th17 cells during the course of the disease [57].
These findings were later confirmed with p28 / mice, which
showed an increased EAE clinical score accompanied with enhanced
Th17 responses [42]. IL-27 was further shown to negatively regulate
the development of Th17 cells in a rodent model of uveitis,
called experimental autoimmune uveoretinitis (EAU) [58]. These
data convincingly show that IL-27 acts as a natural antagonist of
Th17 cells.
6. Chronic inflammation and cancer
IL-27 is strongly involved in controlling a regulated response
to pathogens and avoiding overwhelming inflammations after
infection. Nevertheless there are data that point out a role for this
cytokine in the pathologies of chronic inflammation and malignant
transformation.
The transcript levels of p28 as well as EBI3 are elevated in
inflamed mucosal tissue of patients with Crohn’s disease but not of
patients with ulcerative colitis. The production of IL-27 but also
IL-23 in these tissues seems to trigger the Th1 response by
inducing the upregulation of IFN-g production and under those
circumstances IL-27 would prolong the inflammatory response
instead of attenuating it [59]. On the other hand it was shown that
STAT3 activation in intestinal epithelial cells that could amongst
others be induced by IL-27 is necessary for the regeneration in
inflammatory bowel diseases. Mice with a tissue-specific knock
out for STAT3 in the intestinal epithelium show less regeneration
but also a minor tumor number [60,61]. The cytokine that is mainly
responsible for this STAT3 activation is IL-6 but as IL-27 is present
in the gut epithelium regulated levels of this cytokine could shape
the IL-6-induced signal transduction.
As IL-27 induces the phosphorylation of STAT3 via its cell
surface receptors it would be reasonable that it would have tumor
promoting effects as STAT3 is considered an oncogene with
known activating mutations that lead to transformation [62–64].
Consequently IL-27 transgenic mice show splenomegalie due to
extramedullar hematopoiesis and also transforming mutations in
WSX-1 can lead to hematologic malignancies through homo-
dimerization of the receptor and subsequent STAT3 activation
[65,66]. Due to its pro-proliferative actions on various immune
cells IL-27 might thus contribute to hematopoietic neoplasms
under certain circumstances.
However, there are many reports that show a beneficial effect of
IL-27 in terms of tumor development, which is not necessarily
contradictory because it induces an antitumor immunity through
CD8+ T cells, NK or NKT cells [67]. In a murine colon carcinoma
model the mice survived healthily when the tumor cells were
overexpressing IL-27 and this was dependent on CD8+ T cells and
IFN-g [67]. In a murine neuroblastoma model it could be shown
that IL-27 in combination with IL-2 induced a potent antitumor
immunity that resulted in complete regression of the tumor and
long-term survival of the mice [68]. In prostate tissue from
patients, WSX-1 was expressed by normal epithelia and in prostate
cancer the expression of WSX-1 was lost during development of
the tumors. However, in early stages IL-27 reduced proliferation
and vascularization and had also an immune-stimulatory effect on
the tumor microenvironment which might even be beneficial for
patients with late stage tumors [69].
The functions of IL-27 in the context of malignant transforma-
tion depend thus strongly on the interaction with the tumor
microenvironment.
7. What is an appropriate IL-27 knock-out mouse?
Knock-out mice are an essential scientific tool to study the
function of a cytokine in vivo. Studying for example IL-6 is rather
straight forward, because the single knock-out of the il6 gene is
sufficient to generate a mouse that lacks just this particular
cytokine, without influencing other cytokines [70]. However, the
generation of il6ra / mice revealed striking differences with
regard to wound healing when compared to il6 / mice, suggesting
additional functions of the IL-6R which are independent of IL-6
[71]. Indeed, both ciliary neurotrophic factor (CNTF) and p28
(IL-30) have been described as cytokines that can signal via the
IL-6R [8,10,72,73]. Differences between the functions of IL-6 and
 S. Aparicio-Siegmund, C. Garbers / Cytokine & Growth Factor Reviews 26 (2015) 579–586
IL-6R in mice have also been reported for the recovery from
dextran sodium sulfate-induced colitis [74].
Dissecting the in vivo functions of IL-27 is much more complex,
because the cytokine/cytokine receptor system consists of four
different proteins, namely p28 and EBI3 (which form the
heterodimeric cytokine) and gp130 and WSX-1, which constitute
the b-receptor heterodimer [1,24]. In principle, genetic deletion of
one of the four genes would result in a knock-out mouse that is
deficient for IL-27. Indeed, all four knock-out mice have already
been generated, but none of these mice is a true and sole knock-out
for IL-27 (Table 1).
Ebi3 / mice are viable and fertile, but show reduced numbers
of invariant natural killer T cells, which is accompanied by
impaired IL-4 production, but normal levels of IFN-g, underlining
an important role for EBI3 in the Th2 differentiation of CD4+ T cells
[75]. However, later studies showed that ebi3 / mice displayed a
reduced Th1 and increased Th2 response in a murine asthma
model [76]. When challenged with the intracellular pathogen
L. major, the diminished Th1 response led to enhanced parasite
numbers and increased lesions [77]. However, due to the fact that
EBI3 is shared between IL-27 and IL-35, both cytokines are lost in
the ebi3 / mice, making it impossible to determine their
individual contribution towards the observed phenotype.
Although it is well established that EBI3 and p28 form the
heterodimeric IL-27, both proteins can be secreted independently
of each other, at least in the murine system [1]. This suggests that
also p28 could have biological functions independent of EBI3.
Indeed, p28 has been shown to induce signaling via the IL-6R either
alone or in combination with cytokine-like factor 1 (CLF1)
[8,10,73]. Importantly, these modes of signaling are independent
of WSX-1 10,75]. In contrast, p28 has also been described as an
antagonist of the signaling of various IL-6 family cytokines via
gp130 [78]. Irrespective of the question how these different
observations could be incorporated into one model of the
biological function of p28, these EBI3-independent functions are
lost besides the IL-27-specific functions in p28 / mice. These
mice, which appeared healthy and fertile, have been generated in
order to study IL-27 in vivo [42,79]. However, it is questionable
which definite conclusions can be drawn from these mice, because
they do not represent single IL-27 knock-outs.
The best candidate to date to study IL-27 in vivo are WSX-1 /
mice [51]. The assumption that a genetic knock-out of WSX-1
would be a suitable approach was based on the observation that
IL-27 is the only cytokine of the IL-6/IL-12 superfamily that
engages WSX-1 for signal transduction, and that WSX-1 is the only
b-receptor that is not used by any other cytokine [18]. However,
this view was recently challenged by a report showing that IL-35
signals via a IL-12Rb2/WSX-1 heterodimer on B cells [80], which
would suggest that WSX-1 / mice do not only lack IL-27, but also
IL-35 signaling.
The early embryonic lethality of gp130 / mice underlines the
importance of IL-6 family cytokines for embryogenesis [81]. Due to
this lethality and the fact that the gp130 b-receptor is engaged by
all family members for signaling, gp130 / mice obviously cannot
be used to study the roles of IL-27 in vivo. Besides the complete
knock-out, also conditional gp130 / mice have been generated
Table 1
Knock-out mice affecting IL-27. Targeted deletion of one of the four components of the cytokine/cytokine receptor complex results in the loss of IL-27 function in vivo, but also
affects other cytokines.
Targeted gene Targeting strategy Affected cytokines
ebi3 / Global IL-27/IL-35
p28 / Conditional IL-27/IL-30
WSX-1 / Global IL-27/IL-35
gp130 / Global IL-27 + all IL-6 family cytokines
gp130 / Conditional IL-27 + all IL-6 family cytokines
583
[82]. However, promoter-driven deletion of gp130 in a certain cell
type or tissue might lead to viable and fertile animals, but will also
result in cells that are unresponsive towards all members of the
IL-6 family of cytokines and can also not be used to dissect the
actions of IL-27 in vivo.
8. A role for IL-27 as a therapeutic target?
The view of IL-27 as an anti-inflammatory cytokine in vivo is
largely based on its ability to negatively regulate the development
of Th17 cells in a RORgt-dependent manner and to enhance the
production of IL-10 by T cells [42]. Overshooting neuroinflamma-
tion due to enhanced generation of Th17 cells which lack
components of the IL-27 signaling cascade have been described
in several different mouse models (see Section 5). It is therefore not
surprising that therapeutic approaches which aim at a specific
inhibition of IL-27 would only be effective in a very limited number
of pathophysiological conditions, where IL-27 has a rather pro-
inflammatory effect.
The effects of IL-27 inhibition have been investigated in a mouse
model for the human autoimmune disease multiple sclerosis, called
experimental autoimmune encephalomyelitis (EAE). In order to
block IL-27, mice were treated with inhibitory antibodies that
neutralize p28 [83]. This led to a marked suppression of ongoing EAE
and reduced IFN-g production by T cells. In contrast, experiments
with p28 / mice could not confirm this finding, but rather showed
enhanced susceptibility of p28 / mice to EAE [42]. The notion that
IL-27 acts as a natural brake in EAE was further supported by a study
showing that WSX-1 / mice developed more Th17 cells and were
thus more susceptible to EAE [57]. Thus, an anti-IL-27 directed
therapy might not be appropriate.
The inhibition of IL-27 in arthritis might be a more promising
approach, although the reported data concerning a pro-inflamma-
tory role of IL-27 in arthritis and joint inflammation are conflicting
[35]. Like for EAE, inhibitory antibodies directed against p28 have
been described to be beneficial in an animal model of adjuvant-
induced arthritis [84]. WSX-1 / mice developed delayed arthritis
in proteoglycan-induced arthritis (PGIA), accompanied by reduced
cartilage destruction and less bone erosion, probably through
reduced generation of IFN-g-producing T cells [85]. In line with
this, patients suffering from rheumatoid arthritis (RA) had higher
IL-27 plasma levels compared to healthy controls [86,87], and p28
protein expression was detected in synovial membranes of RA
patients [88]. It was further reported that IL-27 was increased in
synovial fluid of RA patients, although no increase in plasma levels
were found in this study [89]. The expression of IL-27 was
increased by IL-17 in synovial macrophages from RA patients [90].
However, no correlation was found between IL-17 and IL-27
expression in the synovial fluid of RA patients [89].
Another pro-inflammatory role of IL-27 has been described in a
mouse T cell transfer model of colitis [91]. Herein, the authors
could show that transfer of T cells from WSX-1 / mice resulted in
less weight loss and diminished inflammation of the colon. These
findings open up the therapeutic possibility to target IL-27 in
T cell-driven intestinal inflammation [91]. Furthermore, IL-27
plays a critical role in a murine experimental peritonitis model
Phenotype Citation
Viable and fertile [75]
Viable and fertile [42,79]
Viable and fertile [51]
Embryonic lethality [81]
Phenotype depends on targeted cells [82]
584 S. Aparicio-Siegmund, C. Garbers / Cytokine & Growth Factor Reviews 26 (2015) 579–586
induced by cecal ligation and puncture (CLP) [92]. ebi3 / mice
were protected from CLP-induced septic peritonitis, and mice
treated with a fusion protein consisting of the extracellular part of
WSX-1 and the Fc part of an IgG antibody showed increased
survival rates [92].
This strategy to inhibit IL-27 is reminiscent of sgp130Fc, which
blocks signaling of IL-6 in complex with the soluble IL-6R [93,94].
Interestingly, sWSX-1Fc, but not sgp130Fc was not able to block
signaling of IL-27 [95], although gp130 and WSX-1 serve as the
membrane-bound b-receptors, suggesting that the affinity of IL-27
is considerably higher towards WSX-1 than gp130 (Fig. 2). The
different forms of sgp130 that can be found in the circulation at
levels of about 400 ng/ml arise from alternative splicing of the
gp130 mRNA [96]. Recently, a naturally occurring form of human
sWSX-1 has been described, which is generated by CD4+ and CD8+
T cells, B cells, and myeloid cells [97]. In contrast to sgp130, the
authors found no evidence for alternative splicing of the WSX-1
mRNA, but rather showed that metalloproteases were responsible
for the generation of sWSX-1. They reported serum levels of about
10 ng/ml in healthy humans, and an increase in sWSX-1 levels in
the serum of patients suffering from Morbus Crohn [97]. These data
suggest that sWSX-1 acts a natural antagonist of IL-27 signaling in
vivo, comparable to the role of sgp130 for IL-6 trans-signaling
[18,94]. However, given the fact that sgp130 serum levels are 40
fold higher than sWSX-1 serum levels, the question remains under
which conditions this inhibitory capacity plays a functional role.
9. Concluding remarks
The fact that the cytokine IL-27 and its receptor complex are
formed by heterodimers, and thus four different proteins have to
act in concert to initiate signaling, makes IL-27 a very interesting,
but not easy to studying cytokine. Plasticity and crosstalk of the
individual cytokine subunits and the shared use of the b-receptors
with other cytokines of the IL-6/IL-12 superfamily make the
analysis of IL-27 in vivo challenging and difficult [18].
However, since its discovery in 2002 [1], the immunobiology of
IL-27 has been explored in great detail, and the unique role of IL-27
in terms of T cell differentiation, inflammation and infection is
remarkable. Future research will show whether and how inhibition
of IL-27 might be a reasonable therapeutic strategy.
References
[1] S. Pflanz, J.C. Timans, J. Cheung, et al., IL-27, a heterodimeric cytokine
composed of EBI3 and p28 protein, induces proliferation of naive CD4(+) T
cells, Immunity 16 (2002) 779–790.
[2] J.F. Bazan, Haemopoietic receptors and helical cytokines, Immunol. Today 11
(1990) 350–354.
[3] A. Villarino, L. Hibbert, L. Lieberman, et al., The IL-27R (WSX-1) is required to
suppress T cell hyperactivity during infection, Immunity 19 (2003) 645–655.
[4] A.V. Villarino, J.S. Stumhofer, C.J. Saris, R.A. Kastelein, F.J. de Sauvage, C.A.
Hunter, IL-27 limits IL-2 production during Th1 differentiation, J. Immunol.
176 (2006) 237–247.
[5] C. Diveu, M.J. McGeachy, K. Boniface, et al., IL-27 blocks RORc expression to
inhibit lineage commitment of Th17 cells, J. Immunol. 182 (2009) 5748–5756.
[6] L. Hibbert, S. Pflanz, R. De Waal Malefyt, R.A. Kastelein, IL-27 and IFN-alpha
signal via Stat1 and Stat3 and induce T-Bet and IL-12Rbeta2 in naive T cells, J.
Interferon Cytokine Res. 23 (2003) 513–522.
[7] J.S. Stumhofer, A. Laurence, E.H. Wilson, et al., Interleukin 27 negatively
regulates the development of interleukin 17-producing T helper cells during
chronic inflammation of the central nervous system, Nat. Immunol. 7 (2006)
937–945.
[8] S. Crabé, A. Guay-Giroux, A.J. Tormo, et al., The IL-27 p28 subunit binds
cytokine-like factor 1 to form a cytokine regulating NK and T cell activities
requiring IL-6R for signaling, J. Immunol. 183 (2009) 7692–7702.
[9] L.W. Collison, D.A. Vignali, Interleukin-35: odd one out or part of the family?
Immunol. Rev. 226 (2008) 248–262.
[10] C. Garbers, B. Spudy, S. Aparicio-Siegmund, et al., An interleukin-6 receptor-
dependent molecular switch mediates signal transduction of the IL-27
cytokine subunit p28 (IL-30) via a gp130 protein receptor homodimer, J. Biol.
Chem. 288 (2013) 4346–4354.
[11] B.M. Matta, G. Raimondi, B.R. Rosborough, T.L. Sumpter, A.W. Thomson, IL-27
production and STAT3-dependent upregulation of B7-H1 mediate immune
regulatory functions of liver plasmacytoid dendritic cells, J. Immunol. 188
(2012) 5227–5237.
[12] M. Bosmann, N.F. Russkamp, B. Strobl, et al., Interruption of macrophage-
derived IL-27(p28) production by IL-10 during sepsis requires STAT3 but not
SOCS3, J. Immunol. 193 (2014) 5668–5677.
[13] P. Charlot-Rabiega, E. Bardel, C. Dietrich, R. Kastelein, O. Devergne, Signaling
events involved in interleukin 27 (IL-27)-induced proliferation of human naive
CD4+ T cells and B cells, J. Biol. Chem. 286 (2011) 27350–27362.
[14] A.V. Villarino, J. Larkin 3rd, C.J. Saris, et al., Positive and negative regulation of
the IL-27 receptor during lymphoid cell activation, J. Immunol. 174 (2005)
7684–7691.
[15] S. Aparicio-Siegmund, J.M. Moll, J. Lokau, et al., Recombinant p35 from
bacteria can form interleukin (IL-)12, but not IL-35, PLoS ONE 9 (2014)
e107990.
[16] L.W. Collison, C.J. Workman, T.T. Kuo, et al., The inhibitory cytokine IL-35
contributes to regulatory T-cell function, Nature 450 (2007) 566–569.
[17] L. Jones, V. Chaturvedi, C. Uyttenhove, J. Van Snick, D.A. Vignali, Distinct
subunit pairing criteria within the heterodimeric IL-12 cytokine family, Mol.
Immunol. 51 (2012) 234–244.
[18] C. Garbers, H. Hermanns, F. Schaper, et al., Plasticity and cross-talk of
Interleukin 6-type cytokines, Cytokine Growth Factor Rev. 23 (2012) 85–182.
[19] S. Aparicio-Siegmund, J. Sommer, N. Monhasery, et al., Inhibition of protein
kinase II (CK2) prevents induced signal transducer and activator of
transcription (STAT) 1/3 and constitutive STAT3 activation, Oncotarget 5
(2014) 2131–2148.
[20] D. Guschin, N. Rogers, J. Briscoe, et al., A major role for the protein tyrosine
kinase JAK1 in the JAK/STAT signal transduction pathway in response to
interleukin-6, EMBO J. 14 (1995) 1421–1429.
[21] P. Heinrich, I. Behrmann, S. Haan, H. Hermanns, G. Müller-Newen, F. Schaper,
Principles of interleukin (IL)-6-type cytokine signalling and its regulation,
Biochem. J. 374 (2003) 1–20.
[22] S. Lucas, N. Ghilardi, J. Li, F.J. de Sauvage, IL-27 regulates IL-12 responsiveness
of naive CD4+ T cells through Stat1-dependent and -independent mechanisms,
Proc. Natl. Acad. Sci. U.S.A. 100 (2003) 15047–15052.
[23] J. Diegelmann, T. Olszak, B. Göke, S. Blumberg, R.S. Brand, A novel role for
interleukin-27 (IL-27) as mediator of intestinal epithelial barrier protection
mediated via differential signal transducer and activator of transcription
(STAT) protein signaling and induction of antibacterial and anti-inflammatory
proteins, J. Biol. Chem. (2012).
[24] S. Pflanz, L. Hibbert, J. Mattson, et al., WSX-1 and glycoprotein 130 constitute
a signal-transducing receptor for IL-27, J. Immunol. 172 (2004) 2225–2231.
[25] T. Owaki, M. Asakawa, F. Fukai, J. Mizuguchi, T. Yoshimoto, IL-27 induces
Th1 differentiation via p38 MAPK/T-bet- and intercellular adhesion
molecule-1/LFA-1/ERK1/2-dependent pathways, J. Immunol. 177 (2006)
7579–7587.
[26] N.J. Kershaw, J.M. Murphy, N.P. Liau, et al., SOCS3 binds specific receptor-JAK
complexes to control cytokine signaling by direct kinase inhibition, Nat.
Struct. Mol. Biol. 20 (2013) 469–476.
[27] J.J. Babon, L.N. Varghese, N.A. Nicola, Inhibition of IL-6 family cytokines by
SOCS3, Semin. Immunol. 26 (2014) 13–19.
[28] H. Yasukawa, M. Ohishi, H. Mori, et al., IL-6 induces an anti-inflammatory
response in the absence of SOCS3 in macrophages, Nat. Immunol. 4 (2003)
551–556.
[29] S.E. Nicholson, D. De Souza, L.J. Fabri, et al., Suppressor of cytokine signaling-3
preferentially binds to the SHP-2-binding site on the shared cytokine receptor
subunit gp130, Proc. Natl. Acad. Sci. U.S.A. 97 (2000) 6493–6498.
[30] K. Hirahara, A. Onodera, A.V. Villarino, et al., Asymmetric action of STAT
transcription factors drives transcriptional outputs and cytokine specificity,
Immunity 42 (2015) 877–889.
[31] Y. Qiao, E.G. Giannopoulou, C.H. Chan, et al., Synergistic activation of
inflammatory cytokine genes by interferon-gamma-induced chromatin
remodeling and toll-like receptor signaling, Immunity 39 (2013) 454–469.
[32] A. Takeda, H. Shinjiro, Y. Atsushi, et al., Cutting edge: role of IL-27/WSX-1
signaling for induction of T-Bet through activation of STAT1 during initial Th1
commitment, J. Immunol. 170 (2003) 4886–4890.
[33] Q. Li, L. Zhang, M. Yang, R. Xia, L. Xia, F. Liu, Increased interleukin-27
promotes Th1 differentiation in patients with chronic immune
thrombocytopenia, Scand. J. Immunol. 80 (2014) 276–282.
[34] S. Kamiya, M. Okumura, Y. Chiba, et al., IL-27 suppresses RANKL expression in
CD4+ T cells in part through STAT3, Immunol. Lett. 138 (2011) 47–53.
[35] I.E. Adamopoulos, S. Pflanz, The emerging role of interleukin 27 in
inflammatory arthritis and bone destruction, Cytokine Growth Factor Rev. 24
(2013) 115–121.
[36] A. Young, E. Linehan, E. Hams, et al., Cutting edge: suppression of GM-CSF
expression in murine and human T cells by IL-27, J. Immunol. 189 (2012)
2079–2083.
[37] S. Aggarwal, N. Ghilardi, M.-H.H. Xie, F.J. de Sauvage, A.L. Gurney, Interleukin-
23 promotes a distinct CD4 T cell activation state characterized by the
production of interleukin-17, J. Biol. Chem. 278 (2003) 1910–1914.
[38] P.R. Mangan, L.E. Harrington, D.B. O’Quinn, et al., Transforming growth factor-
beta induces development of the T(H)17 lineage, Nature 441 (2006) 231–234.
[39] E. Bettelli, Y. Carrier, W. Gao, et al., Reciprocal developmental pathways for
the generation of pathogenic effector TH17 and regulatory T cells, Nature 441
(2006) 235–238.
 S. Aparicio-Siegmund, C. Garbers / Cytokine & Growth Factor Reviews 26 (2015) 579–586
[40] G.W. Jones, R.M. McLoughlin, V.J. Hammond, et al., Loss of CD4+ T cell IL-6R
expression during inflammation underlines a role for IL-6 trans signaling in
the local maintenance of Th17 cells, J. Immunol. 184 (2010) 2130–2139.
[41] A. Kimura, T. Naka, T. Kishimoto, IL-6-dependent and -independent pathways
in the development of interleukin 17-producing T helper cells, Proc. Natl.
Acad. Sci. U.S.A. 104 (2007) 12099–12104.
[42] C. Diveu, M.J. McGeachy, K. Boniface, et al., IL-27 blocks RORc expression to
inhibit lineage commitment of Th17 cells, J. Immunol. (Baltimore Md.: 1950)
182 (2009) 5748–5756.
[43] K. Hirahara, K. Ghoreschi, X.-P.P. Yang, et al., Interleukin-27 priming of T cells
controls IL-17 production in trans via induction of the ligand PD-L1, Immunity
36 (2012) 1017–1030.
[44] M. El-behi, B. Ciric, S. Yu, G.-X.X. Zhang, D.C. Fitzgerald, A. Rostami,
Differential effect of IL-27 on developing versus committed Th17 cells,
J. Immunol. 183 (2009) 4957–4967.
[45] C. Neufert, C. Becker, S. Wirtz, et al., IL-27 controls the development of
inducible regulatory T cells and Th17 cells via differential effects on STAT1,
Eur. J. Immunol. 37 (2007) 1809–1816.
[46] D.C. Fitzgerald, G.X. Zhang, M. El-Behi, Suppression of autoimmune
inflammation of the central nervous system by interleukin 10 secreted by
interleukin 27-stimulated T cells, Nat. Immunol. 8 (12) (2007) 1372–1379.
[47] J.S. Stumhofer, J.S. Silver, A. Laurence, et al., Interleukins 27 and 6 induce
STAT3-mediated T cell production of interleukin 10, Nat. Immunol. 8 (2007)
1363–1371.
[48] J. Banchereau, V. Pascual, A. O’Garra, From IL-2 to IL-37: the expanding
spectrum of anti-inflammatory cytokines, Nat. Immunol. 13 (2012) 925–931.
[49] C. Pot, H. Jin, A. Awasthi, et al., Cutting edge: IL-27 induces the transcription
factor c-Maf, cytokine IL-21, and the costimulatory receptor ICOS that
coordinately act together to promote differentiation of IL-10-producing Tr1
cells, J. Immunol. 183 (2009) 797–801.
[50] C. Heinemann, S. Heink, F. Petermann, et al., IL-27 and IL-12 oppose pro-
inflammatory IL-23 in CD4+ T cells by inducing Blimp1, Nat. Commun. 5
(2014) 3770.
[51] H. Yoshida, S. Hamano, G. Senaldi, et al., WSX-1 is required for the initiation
of Th1 responses and resistance to L. major infection, Immunity 15 (2001)
569–578.
[52] D. Artis, L.M. Johnson, K. Joyce, et al., Cutting edge: early IL-4 production
governs the requirement for IL-27-WSX-1 signaling in the development
of protective Th1 cytokine responses following Leishmania major infection,
J. Immunol. 172 (2004) 4672–4675.
[53] L.E. Rosas, A.A. Satoskar, K.M. Roth, et al., Interleukin-27R (WSX-1/T-cell
cytokine receptor) gene-deficient mice display enhanced resistance to
leishmania donovani infection but develop severe liver immunopathology, Am.
J. Pathol. 168 (2006) 158–169.
[54] S. Hamano, K. Himeno, Y. Miyazaki, K. Ishii, A. Yamanaka, WSX-1 is required
for resistance to Trypanosoma cruzi infection by regulation of proinflammatory
cytokine production, Immunity 19 (2003) 657–667.
[55] A. Bancroft, N. Humphreys, J. Worthington, H. Yoshida, R. Grencis, WSX-1: a
key role in induction of chronic intestinal nematode infection, J. Immunol. 172
(2004) 7635–7641.
[56] D. Artis, A. Villarino, M. Silverman, et al., The IL-27 receptor (WSX-1) is an
inhibitor of innate and adaptive elements of type 2 immunity, J. Immunol. 173
(2004) 5626–5634.
[57] M. Batten, J. Li, S. Yi, et al., Interleukin 27 limits autoimmune
encephalomyelitis by suppressing the development of interleukin 17-
producing T cells, Nat. Immunol. 7 (2006) 929–936.
[58] A. Amadi-Obi, C.-R.R. Yu, X. Liu, et al., TH17 cells contribute to uveitis and
scleritis and are expanded by IL-2 and inhibited by IL-27/STAT1, Nat. Med. 13
(2007) 711–718.
[59] C. Schmidt, T. Giese, B. Ludwig, et al., Expression of interleukin 12 related
cytokine transcripts in inflammatory bowel disease: elevated interleukin
23p19 and interleukin 27p28 in Crohn’s disease but not in ulcerative colitis,
Inflamm. Bowel Dis. 11 (2005) 16–23.
[60] S. Grivennikov, E. Karin, J. Terzic, et al., IL-6 and Stat3 are required for survival
of intestinal epithelial cells and development of colitis-associated cancer,
Cancer Cell 15 (2009) 103–113.
[61] J. Bollrath, T.J. Phesse, V.A. von Burstin, et al., gp130-mediated Stat3 activation
in enterocytes regulates cell survival and cell-cycle progression during colitis-
associated tumorigenesis, Cancer Cell 15 (2009) 91–102.
[62] J. Bromberg, Stat proteins and oncogenesis, J. Clin. Invest. 109 (2002)
1139–1142.
[63] J. Bromberg, M. Wrzeszczynska, G. Devgan, et al., Stat3 as an oncogene, Cell 98
(1999) 295–303.
[64] C. Pilati, M. Amessou, M. Bihl, et al., Somatic mutations activating STAT3 in
human inflammatory hepatocellular adenomas, J. Exp. Med. 208 (2011)
1359–1366.
[65] J. Seita, M. Asakawa, J. Ooehara, et al., Interleukin-27 directly induces
differentiation in hematopoietic stem cells, Blood 111 (2008) 1903–1912.
[66] Q.T. Lambert, A. Pradhan, J.D. Roll, G.W. Reuther, Mutations in the
transmembrane and juxtamembrane domains enhance IL27R transforming
activity, Biochem. J. 438 (2011) 155–164.
[67] M. Hisada, S. Kamiya, K. Fujita, et al., Potent antitumor activity of interleukin-
27, Cancer Res. 64 (2004) 1152–1156.
[68] R. Salcedo, J.A. Hixon, J.K. Stauffer, et al., Immunologic and therapeutic synergy
of IL-27 and IL-2: enhancement of T cell sensitization, tumor-specific CTL
585
reactivity and complete regression of disseminated neuroblastoma metastases
in the liver and bone marrow, J. Immunol. 182 (2009) 4328–4338.
[69] E. Di Carlo, C. Sorrentino, A. Zorzoli, et al., The antitumor potential of
Interleukin-27 in prostate cancer, Oncotarget 5 (2014) 10332–10341.
[70] M. Kopf, H. Baumann, G. Freer, et al., Impaired immune and acute-phase
responses in interleukin-6-deficient mice, Nature 368 (1994) 339–342.
[71] M. McFarland-Mancini, H. Funk, A. Paluch, et al., Differences in wound healing
in mice with deficiency of IL-6 versus IL-6 receptor, J. Immunol. 184 (2010)
7219–7228.
[72] B. Schuster, M. Kovaleva, Y. Sun, et al., Signaling of human ciliary neurotrophic
factor (CNTF) revisited. The interleukin-6 receptor can serve as an alpha-
receptor for CTNF, J. Biol. Chem. 278 (2003) 9528–9535.
[73] A. Tormo, Y. Meliani, L. Beaupré, et al., The composite cytokine p28/cytokine-
like factor 1 sustains B cell proliferation and promotes plasma cell
differentiation, J. Immunol. 191 (2013) 1657–1665.
[74] J. Sommer, E. Engelowski, P. Baran, C. Garbers, D.M. Floss, J. Scheller,
Interleukin-6, but not the interleukin-6 receptor plays a role in recovery from
dextran sodium sulfate-induced colitis, Int. J. Mol. Med. 34 (2014) 651–660.
[75] E.E. Nieuwenhuis, M.F. Neurath, N. Corazza, et al., Disruption of T helper
2-immune responses in Epstein-Barr virus-induced gene 3-deficient mice,
Proc. Natl. Acad. Sci. U.S.A. 99 (2002) 16951–16956.
[76] E. Dokmeci, L. Xu, E. Robinson, K. Golubets, K. Bottomly, C.A. Herrick,
EBI3 deficiency leads to diminished T helper type 1 and increased T
helper type 2 mediated airway inflammation, Immunology 132 (2011)
559–566.
[77] S. Zahn, S. Wirtz, M. Birkenbach, R.S. Blumberg, M.F. Neurath, E. von Stebut,
Impaired Th1 responses in mice deficient in Epstein-Barr virus-induced gene 3
and challenged with physiological doses of Leishmania major, Eur. J. Immunol.
35 (2005) 1106–1112.
[78] J.S. Stumhofer, E.D. Tait, W.J. Quinn, et al., A role for IL-27p28 as an antagonist
of gp130-mediated signaling, Nat. Immunol. 11 (2010) 1119–1126.
[79] S. Zhang, R. Liang, W. Luo, et al., High susceptibility to liver injury in IL-27 p28
conditional knockout mice involves intrinsic interferon-g dysregulation of
CD4+ T cells, Hepatology 57 (2013) 1620–1631.
[80] R.-X.X. Wang, C.-R.R. Yu, I.M. Dambuza, et al., Interleukin-35 induces
regulatory B cells that suppress autoimmune disease, Nat. Med. 20 (2014)
633–641.
[81] K. Yoshida, T. Taga, M. Saito, Targeted disruption of gp130, a common
signal transducer for the interleukin 6 family of cytokines, leads to
myocardial and hematological disorders, Proc. Natl. Acad. Sci. U.S.A. 93
(1996) 407–411.
[82] U.A. Betz, W. Bloch, M. van den Broek, et al., Postnatally induced inactivation of
gp130 in mice results in neurological, cardiac, hematopoietic, immunological,
hepatic, and pulmonary defects, J. Exp. Med. 188 (1998) 1955–1965.
[83] R. Goldberg, Y. Zohar, G. Wildbaum, Y. Geron, G. Maor, N. Karin,
Suppression of ongoing experimental autoimmune encephalomyelitis by
neutralizing the function of the p28 subunit of IL-27, J. Immunol. 173 (2004)
6465–6471.
[84] R. Goldberg, G. Wildbaum, Y. Zohar, G. Maor, N. Karin, Suppression of ongoing
adjuvant-induced arthritis by neutralizing the function of the p28 subunit of
IL-27, J. Immunol. 173 (2004) 1171–1178.
[85] Y. Cao, P.D. Doodes, T.T. Glant, A. Finnegan, IL-27 induces a Th1 immune
response and susceptibility to experimental arthritis, J. Immunol. 180 (2008)
922–930.
[86] C.K. Wong, D.P. Chen, a.P. Tam, L.S. Li, E.K. Yin, Y.B.C.W. Lam, Effects of
inflammatory cytokine IL-27 on the activation of fibroblast-like synoviocytes
in rheumatoid arthritis, Arthritis Res. Ther. (2010) 12.
[87] H. Shen, L. Xia, W. Xiao, J. Lu, Increased levels of interleukin-27 in patients
with rheumatoid arthritis, Arthritis Rheum. 63 (2011) 860–861.
[88] W. Niedbala, B. Cai, X. Wei, et al., Interleukin 27 attenuates collagen-induced
arthritis, Ann. Rheum. Dis. 67 (2008) 1474–1479.
[89] S. Tanida, H. Yoshitomi, M. Ishikawa, T. Kasahara, IL-27-producing CD14+ cells
infiltrate inflamed joints of rheumatoid arthritis and regulate inflammation
and chemotactic migration, Cytokine 55 (2011) 237–244.
[90] S.H. Baek, S.G. Lee, Y.E. Park, G.T. Kim, C.D. Kim, S.Y. Park, Increased synovial
expression of IL-27 by IL-17 in rheumatoid arthritis, Imflamm. Res. 61 (2012)
1339–1345.
[91] J.H. Cox, N.M. Kljavin, N. Ramamoorthi, L. Diehl, M. Batten, N. Ghilardi, IL-27
promotes T cell-dependent colitis through multiple mechanisms, J. Exp. Med.
208 (2011) 115–123.
[92] S. Wirtz, I. Tubbe, P.R. Galle, et al., Protection from lethal septic peritonitis by
neutralizing the biological function of interleukin 27, J. Exp. Med. 203 (2006)
1875–1881.
[93] S.A. Jones, J. Scheller, S. Rose-John, Therapeutic strategies for the clinical
blockade of IL-6/gp130 signaling, J. Clin. Invest. 121 (2011) 3375–3383.
[94] C. Garbers, S. Aparicio-Siegmund, S. Rose-John, The IL-6/gp130/STAT3 signaling
axis: recent advances towards specific inhibition, Curr. Opin. Immunol. 34
(2015) 75–82.
[95] J. Scheller, B. Schuster, C. Hölscher, T. Yoshimoto, S. Rose-John, No inhibition
of IL-27 signaling by soluble gp130, Biochem. Biophys. Res. Commun. 326
(2005) 724–728.
[96] J. Wolf, S. Rose-John, C. Garbers, Interleukin-6 and its receptors: a highly
regulated and dynamic system, Cytokine 70 (2014) 11–20.
[97] C. Dietrich, S. Candon, F.M. Ruemmele, O. Devergne, A soluble form of IL-27Ra
is a natural IL-27 antagonist, J. Immunol. 192 (2014) 5382–5389.
586 S. Aparicio-Siegmund, C. Garbers / Cytokine & Growth Factor Reviews 26 (2015) 579–586
Samadhi Aparicio Siegmund studied biochemistry
and molecular biology at Kiel University, Germany and
at the Technical University Valencia, Spain and received
her diploma degree in 2010. She joined the Institute of
Biochemistry and Molecular Biology II at the Heinrich-
Heine-University in Düsseldorf, Germany in 2011
where she obtained her Dr. rer. nat. (Ph.D.) in 2015.
Since 2014 she is working at Kiel University, Germany
in the group ‘‘Cytokine and Metalloproteinase Re-
search’’ at the Institute of Biochemistry as a postdoc-
toral research associate. Her current interests are
focused on the signal transduction and cross-talk of
IL-6- and IL-12-type cytokines.
Christoph Garbers received his diploma degree in
Pharmacy in 2007 at Kiel University, Germany, and his
licensure as pharmacist in 2008. He joined the group
‘‘Cytokine and Metalloproteinase Research’’ at the
Institute of Biochemistry of Kiel University in 2008
and obtained his Dr. rer. nat. (Ph.D.) in 2011. He then
moved to the Heinrich-Heine-University Düsseldorf,
Germany, to work at the Institute of Biochemistry and
Molecular Biology II. Since 2013, he heads his own
research group, again at the Institute of Biochemistry at
Kiel University. His current interests are focused on
limited proteolysis of cytokine receptors, plasticity of
cytokines and cytokine receptors, and signal transduc-
tion of IL-6 type cytokines.