Interleukin-6 biology is coordinated by membrane-bound and
soluble receptors: role in inflammation and cancer
Stefan Rose-John,*,1Ju ¨rgen Scheller,* Greg Elson,†and Simon A. Jones‡
*Biochemisches Institut, Christian-Albrechts-Universita ¨t zu Kiel, Germany;†NovImmune SA, Geneva, Switzerland;
and‡Department of Medical Biochemistry and Immunology, The School of Medicine Cardiff University, Wales,
brane-bound and soluble forms, bind their ligands
with comparable affinity. Although most soluble re-
ceptors are antagonists and compete with their mem-
brane-associated counterparts for the ligands, cer-
tain soluble receptors are agonists. In these cases,
complexes of ligand and soluble receptor bind on
target cells to second receptor subunits and initiate
intracellular signaling. The soluble receptors of the
interleukin (IL)-6 family of cytokines (sIL-6R, sIL-
11R, soluble ciliary neurotrophic factor receptor)
are agonists capable of transmitting signals through
interaction with the universal signal-transducing re-
ceptor for all IL-6 family cytokines, gp130. In vivo,
the IL-6/sIL-6R complex stimulates several types of
cells, which are unresponsive to IL-6 alone, as they
cytokine receptors occurs via two distinct mecha-
nisms—limited proteolysis and translation—from dif-
ferentially spliced mRNA. We have demonstrated
that a soluble form of the IL-6 family signaling recep-
tor subunit gp130, which is generated by differential
splicing, is the natural inhibitor of IL-6 trans-signal-
ing responses. We have shown that in many chronic
inflammatory diseases, including chronic inflamma-
tory bowel disease, peritonitis, rheumatoid arthritis,
asthma, as well as colon cancer, IL-6 trans-signaling
is critically involved in the maintenance of a disease
state, by promoting transition from acute to chronic
inflammation. Moreover, in all these models, the
course of the disease can be disrupted by specifically
interfering with IL-6 trans-signaling using the soluble
gp130 protein. The pathophysiological mechanisms
by which the IL-6/sIL-6R complex regulates the in-
flammatory state are discussed. J. Leukoc. Biol. 80:
Cytokine receptors, which exist in mem-
Key Words: cytokine ? cytokine receptor ? gp130 ? sgp130Fc fusion
Cytokines of the interleukin-6 (IL-6) family act via receptor
complexes containing at least one subunit of the signal-trans-
ducing protein gp130 . The family comprises IL-6, IL-11,
ciliary neurotrophic factor (CNTF), cardiotrophin-1 (CT-1),
cardiotrophin-like cytokine (CLC), leukemia inhibitory factor
(LIF), neuropoietin (NPN), and oncostatin M (OSM) [1, 2] and
has recently been supplemented by the addition of two newly
characterized cytokines IL-27 and IL-31 [3, 4]. IL-6, IL-11,
and CNTF first bind to specific receptors, and these complexes
associate with a homodimer of gp130 in the case of IL-6 and
IL-11 or alternatively, with a heterodimer of gp130 and the
related protein LIF receptor (LIF-R) in the case of CNTF, CLC,
and NPN. OSM and LIF first bind directly to gp130 and LIF-R,
respectively, and form heterodimers with LIF-R and gp130. In
addition to signaling via a LIF-R/gp130 heterodimer, OSM can
bind a gp130-related receptor (OSM-R?), which again, het-
erodimerizes with gp130 to trigger OSM-mediated events .
This alternative OSM-R also interacts with an IL-31-binding
protein to form an IL-31-specific receptor complex . CT-1
binds directly to the LIF-R and induces gp130/LIF-R het-
erodimer formation , and the presence of an additional
glycosylphosphatidylinositol-anchored receptor specific for
CT-1 on neural cells has been hypothesized recently .
On target cells, IL-6 first binds to the IL-6 receptor (IL-6R).
The complex of IL-6 and IL-6R associates with the signal-
transducing membrane protein gp130, thereby promoting its
dimerization and the subsequent initiation of intracellular sig-
naling [1, 7]. gp130 is expressed by most, if not all, cells in the
body, whereas IL-6R is mainly expressed by hepatocytes,
neutrophils, monocytes/macrophages, and some lymphocytes.
A naturally occurring, soluble form of the IL-6R (sIL-6R),
which has been found in various body fluids, is generated by
two independent mechanisms: limited proteolysis of the mem-
brane protein and translation from an alternatively spliced
mRNA [8–15]. It is interesting that sIL-6R together with IL-6
stimulate cells, which only express gp130 [16, 17], a process
that is now termed trans-signaling [16–18] (Fig. 1A).
Recently, it has been shown that the sIL-6R strongly sensi-
tizes target cells . Embryonic stem cells [20, 21], early
hematopoietic progenitor cells [22–26], T cells [27–29], many
neural cells [30, 31], smooth muscle cells , mesothelial
1Correspondence: Institut fu ¨r Biochemie, Christian-Albrechts-Universita ¨t
Kiel,Olshausenstr. 40, D-24098
Received November 17, 2005; revised April 9, 2006; accepted April 19,
2006; doi: 10.1189/jlb.1105674.
0741-5400/06/0080-227 © Society for Leukocyte Biology
Journal of Leukocyte Biology
Volume 80, August 2006
cells [33, 34], and endothelial cells , among others, are
only responsive to IL-6 in the presence of sIL-6R . The
fact that IL-6/sIL-6R promotes wound healing strongly ar-
gues that keratinocytes may also be subject to trans-signal-
ing processes .
It is interesting that we recently showed that CNTF not only
acts via the membrane-bound or soluble CNTF-R (sCNTF-R)
but can elicit responses through direct binding to membrane-
bound and sIL-6R . This may have important implications
for the use of CNTF as a therapeutic agent in neurodegenera-
tive diseases  and for the treatment of obesity . The use
of CNTF as a drug in amytrophic lateral sklerosis had to be
discontinued as a result of severe peripheral side-effects.
This was surprising, as the CNTF-R is not widely expressed
outside of the central nervous system. The fact that CNTF
can also signal via the IL-6R may explain most if not all of
these side-effects and will be the basis for the construction
of CNTF variants, which only bind to the CNTF-R but not to
the IL-6R .
THE CONCEPT OF DESIGNER CYTOKINES
Using the structural information available on membrane-bound
and soluble cytokine receptors, we have constructed chimeric
proteins in which receptor recognition modules have been
altered or exchanged and/or in which cytokines have been
fused to their soluble cytokine receptors. Furthermore, chi-
meric receptor proteins have been constructed, which contain
cytokine-binding modules of gp130, LIF-R, or OSM-Rß. This
approach has allowed the definition of cytokine-binding mod-
ules on receptor proteins [40–44].
We have also constructed a fusion protein consisting of the
domains of IL-6 and sIL-6R, which are necessary for biological
activity. The engineering of this chimeric protein has been per-
formed through covalently linking the two functional proteins via
a flexible polypeptide linker. The resulting recombinant protein
was found to be 100–1000 times more active than the native
termed Hyper-IL-6 . Many cells, including hematopoietic
progenitor cells, neuronal cells, endothelial cells, smooth muscle
cells, and embryonic stem cells, which do not respond to IL-6
alone, show a remarkable response to IL-6/sIL-6R [18, 21, 25,
45–48]. Recently, our approach has been adopted to construct a
fusion protein between IL-11 and sIL-11R . A designer cyto-
kine consisting of CNTF or CLC, fused to the sCNTF-R, has also
been constructed, and these unimolecular proteins exhibit high
neurotrophic activity on cells negative for surface CNTF-R ex-
pression [47, 50].
THE PHYSIOLOGIC ROLE OF sgp130
We have analyzed the role of sgp130 using a recombinant sgp130
protein fused to the Fc region of human immunogloblin G1 .
The sgp130 protein only inhibited the expression of the acute-
phase protein antichymotrypsin in HepG2 cells, which had been
treated with Hyper-IL-6, whereas IL-6-stimulated HepG2 cells
remained unaffected. It turned out that sgp130 exclusively inhib-
ited IL-6 responses mediated by the sIL-6R without interfering
with responses via the membrane-bound IL-6R. sgp130 has been
shown to modulate leukocyte trafficking and to suppress the
33, 52, 53]. Indeed, the phenotype of the response exhibited in
vivo following sgp130 administration often closely resembles
those observed in IL-6-deficient mice. Therefore, we postulated
that sgp130 acts as the natural inhibitor of IL-6/sIL-6R com-
plexes. In this respect, IL-6 does not bind sgp130 directly, and
consequently, it is proposed that classical IL-6 via the cognate
IL-6R and membrane-bound gp130 remain unhindered. Our
model of the molecular mechanism by which sgp130 exerts se-
lective inhibition toward the IL-6/sIL-6R complex is depicted in
Figure 1B. Kinetic appraisal of binding parameters suggest that
the IL-6/sIL-6R complex has equal affinity for membrane-bound
and sgp130 variants, and therefore, a molar excess of sgp130
leads to inhibition of IL-6 trans-signaling [18, 54]. The patho-
physiological consequence of this selective inhibition is out-
sgp130 SPECIFICALLY INHIBITS IL-6
As gp130 is the common receptor subunit of the cytokines
IL-6, IL-11, IL-27, CLC, CNTF, CT-1, LIF, OSM, and NPN, it
Fig. 1. The IL-6R complex, trans-signaling, and the inhibitory mechanism of
soluble gp130 (sgp130). (A) The two modes of IL-6 activation are presented as
classical IL-6 activation via the membrane-bound IL-6R and sIL-6R-mediated
cell signaling (IL-6 trans-signaling). In both cases, responses are elicited
through engagement with membrane-bound gp130. (B) Classical IL-6 signaling
is unaffected by sgp130 yet preferentially binds the IL-6/sIL-6R complex to
antagonize IL-6 trans-signaling.
228 Journal of Leukocyte Biology
Volume 80, August 2006
is reasonable to question whether inhibition by sgp130 is
specific for the IL-6/sIL-6R complex or whether sgp130 also
affects the biologic activity of the other gp130 family cytokines.
We have shown that the activity of CNTF is unaffected by the
sgp130Fc protein. The proliferative activity of LIF and OSM on
BAF/3 cells stably transfected with gp130 and LIF-R cDNAs
is only inhibited by more than 100-fold higher sgp130Fc
concentrations than those needed to inhibit Hyper-IL-6 [51,
55]. This was corroborated by surface plasmon resonance,
which shows that Hyper-IL-6 and OSM bind sgp130 with
dissociation constant values of 6.9 ? 10?9M and 1.6 ? 10?7
M, respectively . The cytokine IL-27 has recently been
found to act via a receptor complex consisting of gp130 and the
related receptor protein WSX-1 . We therefore addressed
the question of whether sgp130Fc exhibited an inhibitory effect
on the activity of IL-27. We could clearly show that the
sgp130Fc protein did not affect the IL-27-mediated signal
transducer and activator of transcription 3 (STAT3) phosphor-
ylation and proliferation of BAF/3 cells expressing gp130 and
WSX-1 . We concluded from these results that the
sgp130Fc protein specifically inhibits the IL-6/sIL-6R trans-
signaling responses .
DEFINING AN INFLAMMATORY CONTEXT
FOR IL-6 TRANS-SIGNALING
Recent advances have documented a series of IL-6 activities,
which are critical for resolving innate immunity and promoting
acquired immunity . Transition between innate and acquired
immunity is a central event in the resolution of any inflammatory
condition, and disruption of this immunological switch may po-
tentially distort the immune response and affect the onset of
autoimmune or chronic inflammatory disorders . Such distor-
tion of the immunological response may provide a viable mecha-
in governing chronic disease progression .
By placing IL-6 trans-signaling within this inflammatory
context, studies are now beginning to comprehend how IL-6
protects against septic shock and directs resolution of acute
inflammation and conversely, elicits detrimental consequences
in more progressive chronic diseases [60–65]. Rationalization
of these IL-6 activities has been aided by advances in our
understanding of the physiological contribution of IL-6 trans-
signaling [27, 33, 52, 66, 67] and by the observed interplay
between IL-6 signaling and STAT1, interferon-?, transforming
growth factor-? (TGF-?), GATA-3, and nuclear factor (NF)-?B
[28, 34, 53, 68–70]. Such interactions appear to influence
disease outcome significantly and have been implicated in the
resolution of acute inflammation, asthma, tumor expansion, and
the inflammatory response associated with tumor progres-
sion [28, 33, 53, 67]. A common feature arising amongst all
of these studies is the role IL-6 trans-signaling performs in
orchestrating leukocyte recruitment, activation, and apo-
ptotic clearance .
Through modulation of inflammatory chemokine expression
and apoptotic control processes, it is evident that IL-6 suppresses
neutrophil infiltration and concurrently promotes the attraction
and activation of mononuclear leukocytes [27, 28, 33, 34, 52, 53,
66–69, 71–73]. Consequently, IL-6 governs the resolution of
acute innate immunity and steers transition to an acquired im-
mune response . The significance of this activity is borne out
in experimental models of colitis and rheumatoid arthritis, where
blockade of sIL-6R-mediated events leads to improved disease
outcome by affecting the recruitment or apoptotic clearance of
mononuclear cells [27, 52]. Retention of an activated mononu-
clear cell population within inflamed tissue represents a clinical
feature of chronic disease progression, and these studies suggest
that IL-6 trans-signaling may contribute to this hallmark of dis-
ease. Credence for this notion is provided by a series of in vitro
and in vivo studies, which have shown IL-6 to rescue T cells from
apoptosis through the STAT3-mediated induction of antiapoptotic
regulators [27, 68, 74–79]. Significant attention has therefore
been given to the IL-6-mediated control of this activated mono-
nuclear cell population .
Through the analysis of mononuclear cell infiltration in
wild-type and IL-6?/?mice, it is evident that IL-6 directs T
cell recruitment by regulating local chemokine secretion [CXC
chemokine ligand 10, CC chemokine ligand 2 (CCL2), CCL4,
CCL5, CCL11, CCL17)] and chemokine receptor [CC chemo-
kine receptor 3 (CCR3), CCR4, CCR5, CXC chemokine recep-
tor 3] expression on the CD3?infiltrate [33, 67]. Documenta-
tion of these activities has been aided by the selective antag-
onism of IL-6 trans-signaling in vivo by sgp130 , which
thus enables responses governed by IL-6 trans-signaling to be
clearly distinguished from those of IL-6 itself. In this respect,
sgp130 blocked chemokine expression selectively but did not
affect T cell chemokine receptor expression . A similar
scenario was also reported in experimental asthma, where IL-6
was shown to direct T helper cell type 2 (Th2) polarization, and
Th2-type responses required IL-6 trans-signaling . Conse-
quently, IL-6 influences T cell responses directly and in con-
junction with its soluble receptor. Such insight leads us to
question whether T cells universally express a cognate IL-6R
or if it defines a specific T cell subset. Comparative analysis of
CD3?T cells from the circulation and at sites of inflammatory
challenge shows that although 35–45% of circulating T cells
express IL-6R, only 2–5% of the CD3?infiltrate are IL-6R?
[27, 28, 79]. Thus, inflammation results in a selective down-
regulation in IL-6R expression or the homing of a CD3?IL-6R–
T cell subset to inflammatory foci. These defined subsets may
represent differences in activation status, as T cells challenged
in vivo with superantigen show significantly lower levels of
IL-6R . Significantly, much debate has focused on whether
IL-6 drives differentiation toward a Th1- or Th2-restricted
phenotype [78, 80–85]. However, the presence of a cognate
IL-6R on Th1 and Th2 cells suggests that IL-6 provides a more
generalized function .
The IL-6-mediated control of cellular differentiation is also
important in the polarization of monocytic cells. Specifically,
IL-6 directs human monocytes away from a dendritic lineage to
a macrophage phenotype [86, 87]. Such skewing of monocytic
differentiation is also evident in vivo, where expansion of bone
marrow-derived dendritic cells (DC) from IL-6?/?mice results
in a tenfold higher number of CD11c?DC than in IL-6?/?
mice . However, the activity of these expanded cells is
impaired, suggesting that IL-6 secretion by these cells may be
necessary for their own activity . Indeed, IL-6 has been
Rose-John et al.
Interleukin-6 acts via membrane-bound and soluble receptors229
shown to inhibit NF-?B activity and to suppress CCR7 expres-
sion in DC , and IL-6 secretion by DC following Toll-like
receptor activation blocks the immunosuppressive activities of
regulatory T cells (Treg) . Thus, IL-6 may influence DC
maturation or trafficking and may be critical in advancing
adaptive immune responses [70, 89].
Overall, these studies have highlighted roles for IL-6 in
innate and acquired immune responses and suggest that inap-
propriate control of these events may contribute to chronic
disease progression. However, with the emergence of IL-6
trans-signaling as an alternative mode of IL-6 activation, it has
become increasingly apparent that selective targeting of sIL-
6R-mediated events may represent a novel avenue for thera-
peutic intervention (Fig. 2).
IL-6 TRANS-SIGNALING IN ARTHRITIS: A
RATIONALE FOR POTENTIAL THERAPEUTIC
Early diagnosis and treatment of rheumatoid arthritis substan-
tially improve disease prognosis and suggest that a targeted
management of initial inflammatory processes is therapeuti-
cally advantageous . Conceptually, this is exemplified by
the selective blockade of inflammatory cytokines, which
through the introduction of novel biologics such as anti-tumor
necrosis factor-? (TNF-?) agents, has led to considerable
clinical benefit . Although this approach has validated the
targeting of inflammatory cytokines as a strategy for treating
ongoing rheumatoid arthritis, the long-term safety and efficacy
of such therapeutic agents remain uncertain. Indeed, the in-
creased association of active tuberculosis with anti-TNF-?
therapy and the inability of certain individuals to respond to
such regimes have highlighted the necessity to identify alter-
native strategies for the management of chronic arthritis.
One factor that has recently received closer inspection is
IL-6. Collective studies have emphasized a central role for IL-6
in governing inflammation and highlight the therapeutic poten-
tial of targeting IL-6 as a strategy for the treatment of chronic
inflammatory diseases. It is significant that IL-6-deficient (IL-
6?/?) mice remain resistant to the induction of a number of
experimental autoimmune conditions [52, 60, 85, 91, 92], and
agents that inhibit IL-6 or its receptor have shown considerable
promise in Phase I and II clinical trials [93–97]. Indeed, the
Fig. 2. Therapeutic strategies for targeting IL-6 signaling. Current therapeutic regimes designed to clinically suppress IL-6 activities involve the application of blocking
monoclonal antibodies (mAb). In particular, Atlizumab/Tocilizumab (MRA) has proven in clinical trials to be effective against a range of conditions. Such approaches,
however, do not delineate between classical IL-6 signaling via its cognate receptor and IL-6 trans-signaling. This regime, therefore, offers a global blockade of IL-6
bioactivity. The natural antagonist sgp130 selectively targets IL-6 trans-signaling and in essence, should leave classical IL-6 signaling intact. This approach influences
a variety of immunological processes and through recent studies, suggests that not all IL-6-mediated events are disturbed by its action. PM, plasma membrane.
230Journal of Leukocyte Biology
Volume 80, August 2006
blocking anti-IL-6R antibody MRA (Atlizumab) is highly ef-
fective in the management of rheumatoid arthritis and Crohn’s
disease and appears well-tolerated with no adverse reports of
infection or toxicity [93, 94]. Results from these trials not only
show improved disease activity but highlight that MRA reduces
the necessity for supplementary anti-inflammatory agents (cor-
ticosteroids or disease-modifying antirheumatic drugs) and also
remains the only anticytokine therapy currently under clinical
investigation, which normalizes levels of acute-phase reactants
in patients with active disease [93, 94]. This infers that an
alteration in IL-6 signaling exacerbates inflammation and per-
petuates chronic disease progression. However, it is unclear
whether blockade of IL-6 bioactivity offers a true advantage
over anti-TNF-? agents, raising the possibility of combination
therapies for selected patient cohorts. To substantiate such a
concept, however, it is essential to understand how in some
cases, cytokines, such as IL-6, direct the inflammatory re-
sponse to ensure successful resolution of a disease process,
and in others, they perpetuate transition to a chronic, inflam-
First indications that IL-6 may have a profound influence on
arthritis progression are derived from the documentation of
extremely high IL-6 concentrations within the serum and sy-
novial fluids of rheumatoid arthritis and juvenile rheumatoid
arthritis patients [98–101]. Such changes infer that IL-6 may
affect systemic events such as high fever, autoantibody pro-
duction, and expression of acute-phase reactants, and localized
increases within the inflamed joint suggest its involvement in
joint pathology [102, 103]. Indeed, a series of in vivo studies
using models of experimental arthritis have now endorsed roles
of IL-6 in joint destruction, leukocyte recruitment, apoptosis,
and T cell activation with IL-6-deficient (IL-6?/?) mice, show-
ing limited or no pathological signs of disease [52, 85, 92,
104–108]. It is significant that the highly protected phenotype
exhibited by IL-6?/?mice is not common to all gp130-acti-
vating cytokines, as OSM-R?- and IL-11R-deficient strains
develop arthritis and show no histological differences com-
pared with wild-type mice . Such findings indicate that
the gp130-mediated responses elicited by IL-6 are unique, and
although blockade of IL-6 signaling is clinically advantageous
in the treatment of rheumatoid arthritis [93, 95–97], enhanced
IL-11 activities appear to suppress arthritis progression [109,
110]. At present, the signaling mechanisms distinguishing
these distinct clinical outcomes remain unclear.
Although IL-6 is considered to play a detrimental role in
arthritis progression, structural cells of the joint (chondrocytes,
synoviocytes, fibroblasts, endothelial cells) lack expression of a
functional, cognate IL-6R [52, 102]. This has highlighted the
necessity to understand the regulation of IL-6-mediated events
and the impact of sIL-6R on arthritic lesions. Elevated sIL-6R
levels have been documented in rheumatoid arthritis and ju-
venile rheumatoid arthritis [52, 102, 111–113], where the
highest levels of sIL-6R and IL-6 are associated with the more
progressive incidences of disease . In this respect, ele-
vated IL-6 and sIL-6R concentrations have been reported to
correlate with the degree of joint destruction typically observed
in rheumatoid arthritis . Indeed, synovial fluids from
rheumatoid arthritis patients containing high levels of IL-6 and
sIL-6R promote osteoclast-like cell formation when added to
cocultures of osteoblastic cells and bone marrow cells . A
role for sIL-6R in bone matrix catabolism is supported further
by the observation that IL-6 trans-signaling promotes collage-
nase-3 release in osteoblasts and proteoglycan synthesis in
chondrocytes and cartilage explants [114–116]. Taken to-
gether, these findings indicate that sIL-6R contributes, at least
in part, to joint destruction.
The presence of elevated sIL-6R levels in arthritic episodes
strongly suggests that sIL-6R production is coordinated as part
of the inflammatory response. Through comparison of sIL-6R
determinations in serum and synovial fluid of patients with
rheumatoid arthritis, it is difficult to judge whether the elevated
sIL-6R levels associated with this disease are derived from
systemic or local sources . However, it is conceivable that
the source of synovial sIL-6R may be derived from activated
leukocytes . This may account for the observed correlation
between leukocyte influx into arthritic joints and the increased
concentration of sIL-6R in synovial fluid . It is significant
that intra-articular administration of IL-6 itself is not sufficient
to restore arthritis severity in IL-6?/?mice primed for antigen-
induced arthritis and does not affect the degree of leukocyte
influx into the joint . Conversely, intra-articular reconsti-
tution of IL-6 trans-signaling with Hyper-IL-6 promotes the
infiltration of CCR2?mononuclear leukocytes and a concur-
rent increase in joint pathology . Thus, regulation of syno-
vial sIL-6R may represent the rate-limiting step in the devel-
opment of joint pathology. It must be stressed, however, that
systemic sIL-6R production may also contribute to the regula-
tion of IL-6 responses in arthritis, as sIL-6R levels are elevated
significantly in systemic onset juvenile chronic arthritis .
Such insight has led us to consider whether preferential
targeting of IL-6 trans-signaling may represent a viable alter-
native strategy for the treatment of rheumatoid arthritis and
other chronic inflammatory disorders [27, 28, 33, 52, 53, 67].
For this purpose, we have elected to use the selective antago-
nistic properties of the naturally occurring sgp130 . As a
strategy, this offers a number of clear advantages, as adminis-
tration of sgp130 can be used to supplement the existing,
circulating levels seen within all individuals and will not result
in a global blockade of all IL-6 responses, which may have
more widespread clinical ramifications. The rationale for this
approach is borne out from the clinical analysis of synovial
IL-6, sIL-6R, and sgp130 levels in rheumatoid arthritis and
osteoarthritis patients . Although IL-6 and sIL-6R concen-
trations were elevated significantly in individuals with rheu-
matoid arthritis, sgp130 levels remained unaltered in both
patient cohorts, suggesting that the regulation of IL-6 trans-
signaling may be distorted in rheumatoid arthritis. To substan-
tiate the validity of this approach, studies exploiting a mono-
articular antigen-induced model of arthritis were adopted [52,
56]. Specifically, histological analysis of joint sections from
IL-6?/?mice treated with an intra-articular dose of sgp130
showed that all parameters of disease severity (leukocyte in-
filtration, synovial hyperplasia, joint erosion, and CCL2 ex-
pression) were suppressed as a result of sgp130 administration
. Indeed, no significant difference was observed between
the histological scores attributed to IL-6?/?mice and those
assigned to IL-6?/?mice exposed to sgp130. It is significant
that several isoforms of sgp130 have been described . One
Rose-John et al.
Interleukin-6 acts via membrane-bound and soluble receptors 231
form, known as gp130-rheumatoid arthritis antigenic peptide-
bearing soluble form (RAPS), has been defined as a rheumatoid
arthritis autoantigen with serum antibodies against gp130-
RAPS, correlating with indices of disease activity . Al-
though the increased incidence of autoantibodies against
gp130-RAPS could not be substantiated in a Caucasian rheu-
matoid arthritis population, this highly truncated sgp130-
spliced variant was found to be highly efficient at blocking joint
pathology and STAT3 activation in antigen-induced arthritis
. Although the significance of these findings needs to be
clarified in more advanced, systemic models of arthritis,
sgp130 may symbolize a valuable addition to the current
arsenal of therapeutics proven to be effective in the manage-
ment of chronic conditions such as rheumatoid arthritis.
MEMBRANE-BOUND AND sIL-6R IN ASTHMA
IL-6 is known to be secreted by cells mediating the innate
immune response. Also, IL-6 induces the expansion of Th
cells, which are a major component of the acquired immune
response . In addition, IL-6 has been shown to be secreted
by activated DC and to suppress the activity of Treg cells
leading to peripheral tolerance . In view of these results, it
was reasonable to investigate the role IL-6 plays in the devel-
opment of asthma. Increased levels of sIL-6R in the airways of
patients with allergic asthma compared with those in controls
have been observed . It is interesting that it turned out that
the proliferation of mucosal Th2 cells depends on IL-6 trans-
signaling via the sIL-6R, whereas the suppression of Treg cells
and the initial stages of Th2 cell development in the lung
depends on gp130 signals mediated by the membrane-bound
IL-6R . This was corroborated by the fact that
CD4?CD25?but not CD4?CD25–lung T cells selectively
expressed the IL-6R and showed IL-6-dependent STAT3 phos-
phorylation. Therefore, one can predict that the treatment of
asthma patients with the sgp130Fc protein would reduce Th2
cells in the lung and that blockade of the membrane-bound
IL-6R by the neutralizing antibody MRA  would increase
the number of Treg cells in the lung, thereby reducing the local
number of CD4?T-effector cells .
IL-6 TRANS-SIGNALING IN COLITIS AND
We have previously demonstrated a functional role for sIL-6R
in chronic inflammatory bowl disease (Crohn’s disease) .
We have shown that T cells from gastric tissue of Crohn’s
disease patients are extremely resistant to apoptosis and show
activation of the Janus tyrosine kinase-STAT signal transduc-
tion pathway. These T cells produce large amounts of IL-6 but
lack membrane-bound IL-6R. It is surprising that treatment of
these cells with a neutralizing mAb to IL-6R induced apopto-
sis. Moreover, treatment of the cells with sgp130 showed the
same effect (Fig. 3). These results demonstrate that IL-6
trans-signaling promotes retention of activated T cells within
gastric tissue from Crohn’s disease patients and is facilitated
through the induction of antiapoptotic regulators. IL-6R shed-
ding is therefore an active process within this condition, and
sIL-6R required for IL-6-dependent gp130 activation is most
likely released by LPMC macrophages or infiltrating neutro-
phils [27, 51]. It is interesting that it was recently reported that
not only levels of IL-6 but also levels of sIL-6R and sgp130 are
elevated in chronic inflammatory bowel diseases and that IL-6
found in the circulation was complexed to sIL-6R and sgp130
In an inflammatory colon cancer model, we could also dem-
onstrate that there is cross-talk between the cytokine TGF-?
and IL-6 (Fig. 4). Using TGF-? transgenic mice and T cell-
specific TGF-?R dominant-negative mice, we could show in
this inflammatory model that reduced stimulation of T cells by
TGF-? resulted in an increase in IL-6 production by these T
cells. It is surprising that we detected a loss of membrane-
bound IL-6R from the cell surface of epithelial cells in tumor
lesions, which was accompanied by an increase of cell surface
expression of the protease ADAM17, responsible for cleavage
of the IL-6R . Tumor growth could not only be inhibited by
a neutralizing antibody directed against the IL-6R but also by
sgp130Fc, strongly arguing that the growth of the tumor was
regulated by IL-6 trans-signaling rather than by classic signal-
ing via the membrane-bound IL-6R [28, 29]. It is intriguing
that in human colon cancer patients, a similar down-regulation
of IL-6R and up-regulation of ADAM17 on the surface of tumor
epithelial cells were observed, implying that a similar mecha-
nism is operating in human and mouse colon cancer develop-
ment . We therefore argue that interrupting IL-6 trans-
signaling with sgp130Fc will be a promising strategy for the
treatment of colon cancer in humans.
Fig. 3. Apoptosis of lamina propria mononuclear cells (LPMC) of Crohn’s
disease patients upon treatment with sgp130. LPMC were isolated and cultured
for 48 h in the presence or absence of 10 ?g/ml of a neutralizing mAb specific
for human IL-6R or 10 ?g/ml sgp130Fc. Subsequently, cells were stained for
annexin V and propidium iodide (PI) and analyzed by fluorescein-activated
cell sorter. The increase in apoptotic (annexin V-positive and PI-negative)
cells is shown. The data presented are means of triplicate measurements with
standard errors shown as vertical bars.
232 Journal of Leukocyte Biology
Volume 80, August 2006
We conclude that sgp130 is the natural inhibitor of sIL-6R-
dependent IL-6 responses. The selective antagonistic proper-
ties of sgp130 can therefore be used in vivo to delineate
between classical IL-6 signaling and IL-6 trans-signaling. Us-
ing this strategy, it is increasingly evident that sgp130 is
effective in blocking immunological processes, which promote
inflammatory disease progression. Such advances have pro-
vided a therapeutic rationale for the administration of sgp130
in a series of chronic inflammatory and autoimmune condi-
The work in the laboratory of S. R-J. and J. S. was supported by
grants from the Deutsche Forschungsgemeinschaft Bonn (Ger-
many), and the Wellcome Trust and the Arthritis Research
Campaign supported the work of S. A. J.
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236 Journal of Leukocyte Biology
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