IL-6 Trans-Signaling via the Soluble IL-6 Receptor: Importance for the Pro-Inflammatory Activities of IL-6.
ABSTRACT Interleukin-6 (IL-6) is a cytokine with many activities. It has functions in the regulation of the immune system and the nervous system. Furthermore, IL-6 is involved in liver regeneration and in the metabolic control of the body. On target cells, IL-6 binds to an 80 kDa IL-6 receptor (IL-6R). The complex of IL-6 and IL-6R associates with a second protein, gp130, which thereupon dimerizes and initiates intracellular signaling. Whereas gp130 is expressed on all cells, IL-6R is only present on few cells in the body including hepatocytes and some leukocytes. Cells, which do not express IL-6R cannot respond to the cytokine, since gp130 alone has no measurable affinity for IL-6. Interestingly, a soluble form of IL-6R (sIL-6R) comprising the extracellular portion of the receptor can bind IL-6 with a similar affinity as the membrane bound IL-6R. The complex of IL-6 and sIL-6R can bind to gp130 on cells, which do not express the IL-6R, and which are unresponsive to IL-6. This process has been called trans-signaling. Here I will review published evidence that IL-6 trans-signaling is pro-inflammatory whereas classic IL-6 signaling via the membrane bound IL-6R is needed for regenerative or anti-inflammatory activities of the cytokine. Furthermore, the detailed knowledge of IL-6 biology has important consequences for therapeutic strategies aimed at the blockade of the cytokine IL-6.
- SourceAvailable from: Maria Thomas[Show abstract] [Hide abstract]
ABSTRACT: Inflammatory processes are associated with compromised metabolism and elimination of drugs in the liver, largely mediated by proinflammatory cytokines, such as interleukin-6 (IL-6). The HepaRG cell line is an established surrogate for primary human hepatocytes (PHH) in drug metabolism and toxicity studies. However, the impact of inflammatory signaling on HepaRG cells has not been well characterized. In this study, the response of primary human hepatocytes and HepaRG cells to IL-6 was comparatively analyzed. For this purpose, broad spectrum gene expression profiling, including acute phase response genes and a large panel of drug metabolizing enzyme and transporter (DMET) genes as well as their modifiers and regulators, was conducted in combination with cytochrome P450 activity measurements. Exposure of PHH and HepaRG cells to IL-6 resulted in highly similar coordinated reduction of DMET mRNA, including major ABCs, CYPs, GSTs, UGTs, and SLCs. Enzyme activities of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP3A4 were reduced upon 48-72 hours exposure to IL-6 in PHH and HepaRG. However, while these effects were not significant in PHH due to large interindividual donor variability, the impact on HepaRG was more pronounced and highly significant, thus emphasizing the advantage of HepaRG as a more reproducible model system. Exposure of HepaRG cells to interleukin-1β and tumor necrosis factor α resulted in similar effects on gene expression and enzyme activities. The present study emphasizes the role of proinflammatory cytokines in the regulation of drug metabolism and supports the use of HepaRG in lieu of PHH to minimize subject variability. The American Society for Pharmacology and Experimental Therapeutics.Drug metabolism and disposition: the biological fate of chemicals 12/2014; · 3.74 Impact Factor
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ABSTRACT: Immune control of infections with viruses or intracellular bacteria relies on cytotoxic CD8(+) T cells that use granzyme B (GzmB) for elimination of infected cells. During inflammation, mature antigen-presenting dendritic cells instruct naive T cells within lymphoid organs to develop into effector T cells. Here, we report a mechanistically distinct and more rapid process of effector T cell development occurring within 18 hr. Such rapid acquisition of effector T cell function occurred through cross-presenting liver sinusoidal endothelial cells (LSECs) in the absence of innate immune stimulation and known costimulatory signaling. Rather, interleukin-6 (IL-6) trans-signaling was required and sufficient for rapid induction of GzmB expression in CD8(+) T cells. Such LSEC-stimulated GzmB-expressing CD8(+) T cells further responded to inflammatory cytokines, eliciting increased and protracted effector functions. Our findings identify a role for IL-6 trans-signaling in rapid generation of effector function in CD8(+) T cells that may be beneficial for vaccination strategies.Cell Reports 09/2014; 8(5). · 7.21 Impact Factor
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ABSTRACT: Bronchopulmonary dysplasia (BPD) is a common chronic lung disease associated with very preterm birth. The major risk factors include lung inflammation and lung immaturity. In addition, genetic factors play an important role in susceptibility to moderate-to-severe BPD. In this study, the aim was to investigate whether common polymorphisms of specific genes that are involved in inflammation or differentiation of the lung have influence on BPD susceptibility. Genes encoding interleukin-6 (IL6) and its receptors (IL6R and IL6ST), IL-10 (IL10), tumor necrosis factor (TNF), and glucocorticoid receptor (NR3C1) were assessed for associations with moderate-to-severe BPD susceptibility. Five IL6, nine IL6R, four IL6ST, one IL10, two TNF, and 23 NR3C1 single nucleotide polymorphisms (SNPs) were analyzed in very preterm infants born in northern Finland (56 cases and 197 controls) and Canada (58 cases and 68 controls). IL-6, TNF and gp130 contents in umbilical cord blood, collected from very preterm infants, were studied for associations with the polymorphisms. Epistasis (i.e., interactions between SNPs in BPD susceptibility) was also examined. SNPs showing suggestive associations were analyzed in additional replication populations from Finland (39 cases and 188 controls) and Hungary (29 cases and 40 controls). None of the studied SNPs were associated with BPD nor were the IL6, TNF or IL6ST SNPs associated with cord blood IL-6, TNF and gp130, respectively. However, epistasis analysis suggested that SNPs in IL6ST and IL10 were associated interactively with risk of BPD in the northern Finnish population; however, this finding did not remain significant after correction for multiple testing and the finding was not replicated in the other populations. We conclude that the analyzed SNPs within IL6, IL6R, IL6ST, IL10, TNF, and NR3C1 were not associated with BPD. Furthermore, there was no evidence that the studied SNPs directly contribute to the cord blood protein contents.BMC Medical Genetics 01/2014; 15(1):120. · 2.45 Impact Factor
Int. J. Biol. Sci. 2012, 8
I In nt te er rn na at ti io on na al l J Jo ou ur rn na al l o of f B Bi io ol lo og gi ic ca al l S Sc ci ie en nc ce es s
2012; 8(9):1237-1247. doi: 10.7150/ijbs.4989
IL-6 Trans-Signaling via the Soluble IL-6 Receptor: Importance for the
Pro-Inflammatory Activities of IL-6
Institute of Biochemistry, Christian-Albrechts-University of Kiel, Kiel, Germany.
Corresponding author: Stefan Rose-John, Department of Biochemistry, Christian-Albrechts-Universität zu Kiel, Olshausenstrasse
40, D-24098 Kiel, Germany, +49-431-880 3336; Fax: +49-431-880 5007; e-mail: email@example.com.
© Ivyspring International Publisher. This is an open-access article distributed under the terms of the Creative Commons License (http://creativecommons.org/
licenses/by-nc-nd/3.0/). Reproduction is permitted for personal, noncommercial use, provided that the article is in whole, unmodified, and properly cited.
Received: 2012.08.06; Accepted: 2012.08.15; Published: 2012.10.24
Interleukin-6 (IL-6) is a cytokine with many activities. It has functions in the regulation of the
immune system and the nervous system. Furthermore, IL-6 is involved in liver regeneration
and in the metabolic control of the body. On target cells, IL-6 binds to an 80 kDa IL-6 receptor
(IL-6R). The complex of IL-6 and IL-6R associates with a second protein, gp130, which
thereupon dimerizes and initiates intracellular signaling. Whereas gp130 is expressed on all
cells, IL-6R is only present on few cells in the body including hepatocytes and some leukocytes.
Cells, which do not express IL-6R cannot respond to the cytokine, since gp130 alone has no
measurable affinity for IL-6. Interestingly, a soluble form of IL-6R (sIL-6R) comprising the
extracellular portion of the receptor can bind IL-6 with a similar affinity as the membrane
bound IL-6R. The complex of IL-6 and sIL-6R can bind to gp130 on cells, which do not express
the IL-6R, and which are unresponsive to IL-6. This process has been called trans-signaling.
Here I will review published evidence that IL-6 trans-signaling is pro-inflammatory whereas
classic IL-6 signaling via the membrane bound IL-6R is needed for regenerative or an-
ti-inflammatory activities of the cytokine. Furthermore, the detailed knowledge of IL-6 biology
has important consequences for therapeutic strategies aimed at the blockade of the cytokine
Key words: IL-6, IL-6 receptor, shedding, soluble receptor, inflammation, inflammation associated
Interleukin-6 (IL-6) is a four-helical protein of
184 amino acids. The cDNA of IL-6 was cloned in 1986
 and it was recognized that IL-6 belonged to a large
family of cytokines, which all shared the four-helical
protein topology . The IL-6 receptor (IL-6R), a pro-
tein with an Ig-fold, binds IL-6 with nanomolar affin-
ity . Binding of IL-6 to the IL-6R does, however, not
lead to signaling. The complex of IL-6 and IL-6R as-
sociates with the protein gp130 thereby inducing its
dimerization and initiating intracellular signaling via
the JAK/STAT pathway . In addition to the activa-
tion of the canonical JAK/STAT pathway, the phos-
phatase SHP-2 is recruited to tyrosine phosphorylated
gp130, becomes phosphorylated by JAK1 and there-
upon mediates the activation of the Ras-Raf-MAPK
signaling pathway [5, 6]. The contribution of the
JAK/STAT pathway and
Ras-Raf-MAPK signaling pathway to pathophysiolo-
gy has been addressed by using mice in which the
portions of gp130, which trigger these respective
pathways have been genetically modified . Using
these mice in models of rheumatoid arthritis led to the
conclusion that the IL-6-gp130-STAT3 axis was fun-
damentally required for the orchestration of the in-
flammatory process in the animals . From these
results it can be expected that also in rheumatoid ar-
the SHP-2 driven
Int. J. Biol. Sci. 2012, 8
thritis patients IL-6 mediated STAT3 activation will
play a key role in the disease .
Interestingly, gp130 is also a receptor subunit of
the receptor complexes for IL-11, ciliary neurotrophic
factor (CNTF), leukemia inhibitory factor (LIF), on-
costatin M (OSM), cardiotrophin-1 (CT-1), cardiotro-
phin like cytokine (CLC) and IL-27. These cytokines
form the gp130 cytokine family .
The receptor subunit gp130 has no measurable
affinity for IL-6 nor the IL-6R . As a consequence,
IL-6 can only bind to and stimulate cells, which ex-
press the IL-6R. Cells, which only express gp130 are
completely unresponsive to IL-6 . Interestingly, a
soluble form of the IL-6R (sIL-6R) has been found in
body fluids such as urine and blood  and it was
shown that in humans, the sIL-6R could be generated
by two different mechanisms, limited proteolysis of
the membrane bound receptor by the metalloprotease
ADAM17  and by translation of a differentially
spliced mRNA . It is thought that regulated gen-
eration of the sIL-6R occurs through shedding rather
than through differential splicing . Interestingly,
in the mouse, only shedding but no differential splic-
ing of the IL-6R mRNA has been detected . The
sIL-6R binds IL-6 with comparable affinity as the
membrane bound IL-6R . Gp130 expressing cells –
even in the absence of IL-6R – can be stimulated by
the complex of IL-6 and sIL-6R  and this process
has been called trans-signaling . In Fig. 1 it is de-
picted that cells which only express gp130 can only be
stimulated by the complex of IL-6 and sIL-6R (right),
whereas cells, which express IL-6R can respond to
IL-6 alone (left).
Shedding of the IL-6R
Using pulse-chase experiments it was demon-
strated that it took 24 h to completely shed the IL-6R
from cells. Stimulation of the cells with the phorbol
ester PMA induced complete loss of the IL-6R from
the cell surface within 1 h [14, 20]. The cleavage site
was determined and it was shown that small deletion
around the cleavage site completely abrogated
PMA-induced shedding . Subsequent studies es-
tablished that treatment of cells with C-reactive pro-
tein (CRP) , bacterial toxins  and cholesterol
depleting agents  as well as treatment of cells with
bacterial metalloproteinases  induced shedding of
the IL-6R. Since most of these treatments interfere
with membrane integrity from the inside or outside it
was hypothesized that also induction of apoptosis,
which leads to reorientation of phosphatidylinositol
within the membrane, might induce shedding of this
cytokine receptor. Indeed, it turned out that early in-
duction of apoptosis led to strong ADAM17 mediated
shedding of the IL-6R . It was established that in
inflammatory processes, shedding of the IL-6R from
neutrophils, which are the first cells to arrive at a site
of damage, leads to the stimulation of endothelial
cells, which do not express IL-6R on the cell surface
and are therefore unresponsive to the cytokine. Stim-
ulation of endothelial cells by the IL-6/sIL-6R com-
plex leads to secretion of the mononuclear cell at-
tracting cytokine MCP-1. Thereby, the shedding of the
IL-6R acts as a gauge for the initial damage reflected
by the numbers of neutrophils attracted .
trans-signaling. IL-6 Classic-signaling requires mem-
brane bound IL-6R and is restricted to hepatocytes,
some epithelial cells and some leukocytes. IL-6
trans-signaling requires sIL-6R and is possible on all cells
of the body since all cells express the gp130 protein.
1. IL-6 classic- signaling and IL-6
Int. J. Biol. Sci. 2012, 8
On CD4-T-cells, IL-6 has been shown to strongly
influence the balance between regulatory T-cells and
TH17-cells . The induction of TH17-cells by IL-6
was strongly increased by the presence of sIL-6R in-
dicating a role for trans-signaling in this process .
Interestingly, sIL-6R is produced by naïve and
memory CD4-T-cells when the T-cell receptor is acti-
vated . It was shown that this local regulation of
sIL-6R activity and IL-6 trans-signaling contributes to
the status of the T-cell response .
A natural soluble form of gp130 (sgp130) is
found in the circulation  at levels around 400
ng/ml. Furthermore, a shorter form of sgp130 was
detected in normal human urine, plasma and the
synovial fluid of patients with rheumatoid arthritis
. This form of sgp130 called gp130-RAPS only
comprises the Ig-like N-terminal domain as well as
the cytokine binding domain of gp130 and therefore
has a molecular weight of only around 50 kDa . It
was shown that like the soluble, entire extracellular
form of sgp130, the shorter form gp130-RAPS could
bind the IL-6/sIL-6R complex . The soluble forms
of sgp130 were found not to be generated by proteo-
lytic cleavage  but rather by translation from al-
ternatively spliced mRNA .
Transgenic strategies to study IL-6
Transgenic mice were generated, which ex-
pressed a cDNA coding for the human sIL-6R from a
liver promoter . Since murine IL-6 does not bind to
the human IL-6R , these mice showed no pheno-
type. However, when mice were injected with human
IL-6 it turned out that the transgenically expressed
sIL-6R protein led to sensitization towards IL-6 and to
stabilization of IL-6 in the blood of the animals .
The sIL-6R transgenic mice were crossed with mice,
which were transgenic for human IL-6 . Double
transgenic IL-6/sIL-6R mice were compared to IL-6
single transgenic mice. It turned out that only double
transgenic IL-6/sIL-6R mice showed massive ex-
tramedullary hematopoiesis  together with hepa-
tocellular proliferation [41, 42]. Since both phenotypes
were not seen in single IL-6 transgenic mice, these
results were the first indication that in vivo the re-
sponse to the IL-6/sIL-6R complex can be substan-
tially different from the response to IL-6 . An ex-
planation for the different response was that (i)
hepatocytes express far more gp130 than IL-6R on
their cell surface. Therefore, stimulation by IL-6 the
presence of sIL-6R leads to far more gp130 dimers
signaling into the cell (Fig. 2). (ii) In addition, we
could show that while stimulation of cells with IL-6
leads to rapid internalization of IL-6  and thereby
to termination of signaling, addition of the
IL-6/sIL-6R complex to cells resulted in very little
internalization and prolonged signaling . The
combination of increased signal strength due to more
gp130 signaling molecules with prolonged signaling
due to reduced internalization resulted not only in a
quantitative but also in a qualitative different cellular
Fig. 2. Receptor distribution IL-6R expressing cells. Most IL-6R expressing cells express far more gp130 than IL-6R. IL-6 stimu-
lation of such cells leads to the activation of only few gp130 molecules. IL-6 in the presence of the sIL-6R, however, will lead to stimulation
of all gp130 molecules leading to a higher signal amplitude.
Int. J. Biol. Sci. 2012, 8
Protein tools to study IL-6 trans-signaling:
Hyper-IL-6, sgp130Fc, L-gp130
When together with Joachim Grötzinger we built
a molecular model of the IL-6/sIL-6R protein complex
 we realized that the C-terminus of the sIL-6R and
the N-terminus of IL-6 were about 40Å apart. We
therefore introduced at the cDNA level a flexible
peptide linker spanning these 40Å between the
C-terminus of the sIL-6R and the N-terminus of IL-6
(Fig. 3A) . On gp130 expressing cells, the resulting
protein called Hyper-IL-6 was shown to be 100-1,000
times more active than the separate proteins IL-6 and
sIL-6R. This could be explained by the fact that the
affinity of IL-6 to IL-6R is in the range of 1 nM
whereas the complex of IL-6/IL-6R binds with 100
times higher affinity to gp130 . Therefore, the
preformed complex in Hyper-IL-6 showed higher
efficacy than the two separate proteins.
Subsequently, the comparison between applica-
tion of IL-6 and Hyper-IL-6 led to the characterization
of many target cells of IL-6 trans-signaling. Cells,
which would only respond to IL-6 in the presence of
the sIL-6R include hematopoietic stem cells ,
many if not all neural cells [48, 49], smooth muscle
cells  and embryonic stem cells [51, 52]. These re-
sults indicated that the IL-6 trans-signaling pathway
was used in many cell types and tissues .
The receptor subunit gp130 does not show any
affinity for IL-6 or IL-6R alone. Only the complex of
IL-6 and IL-6R binds to cellular expressed gp130 
(Fig. 3B). We expressed the extracellular portion of
gp130 as an IgG1-Fc fusion protein (sgp130Fc) and
could show that also the soluble gp130 protein only
interacts with the sIL-6R in the presence of IL-6 .
As a consequence, the soluble gp130 and the sgp130Fc
protein inhibited IL-6 trans-signaling but had no in-
hibitory effect on classic IL-6 signaling, i.e. on the
stimulation of cells by IL-6 via the membrane bound
IL-6R . Interestingly, the soluble gp130 protein did
not show any species specificity: whereas murine IL-6
does not bind to the human IL-6R, the human and
murine IL-6/sIL-6R complex bound to both, human
and murine soluble gp130 . Therefore, the
sgp130Fc protein could be used as a molecular tool to
discriminate between IL-6 classic signaling and IL-6
trans-signaling on human cells as well as in murine
models of human diseases [54, 55]. Interestingly, it
was shown that the sgp130Fc protein did not inhibit
other gp130 cytokines such as CNTF, LIF, OSM and
IL-27 . The reason for this specificity is that these
gp130 cytokines on the cell surface form a complex
with a heterodimer of gp130 with LIF receptor, OSM
receptor or WSX-1, respectively. Therefore the affinity
of these cytokines to the dimeric sgp130 moiety in the
sgp130Fc protein is much lower than to the membrane
bound heterodimers of gp130 with LIF receptor, OSM
receptor or WSX-1, respectively. Therefore, sgp130Fc
fails to compete efficiently with these cell bound re-
ceptor complexes for binding of CNTF, LIF, OSM and
IL-27 and consequently has little or no inhibitory ac-
tivity . Theoretically, an IL-11/sIL-11R complex
could be inhibited by sgp130Fc. But to date, no natu-
rally occurring sIL-11R has been detected neither in
mouse nor in man.
Fig. 3. Designer proteins for the study of IL-6 signaling. (A) Hyper-IL-6 is a fusion protein between the sIL-6R (blue) and IL-6
(brown). In a molecular model, the C-terminus of sIL-6R was 40 Å apart from the N-terminus of IL-6. Therefore, we inserted a flexible
peptide linker between sIL-6R and IL-6 (black) to connect both molecules. (B) The sgp130Fc protein consists of the extracellular portion
of gp130 linked to the Fc domain of a human IgG1 antibody. The sgp130Fc protein blocks IL-6 trans-signaling without affecting IL-6 classic
signaling. (C) In the L-gp130 protein, the entire extracellular portion of gp130 is replaced by the leucine zipper of the Jun protein, leading
to constitutive dimerization and activation of the gp130 protein. This protein can be used to study the effects of permanent gp130
activation in transfected cells or in tissue specific transgenic animals.
Int. J. Biol. Sci. 2012, 8
So far it is unclear how binding of the IL-6/IL-6R
or IL-6/sIL-6R complexes to gp130 leads to the
transmission of the signal into the cell. It is, however,
clear that dimerization of gp130 cannot be sufficient
for signal initiation since gp130 even in the
un-liganded state already forms a dimer [57, 58]. To
address this question a gp130 cDNA was constructed,
in which the entire region coding for the extracellular
portion was replaced by DNA sequences coding for
the leucine-zipper from the Jun protein [59, 60]. The
presence of the jun-leucine-zipper led to IL-6 inde-
pendent dimerization of gp130, activation and phos-
phorylation of JAK kinases and STAT3 and subse-
quently to transcription of STAT3 target genes (Fig.
3C). When transfected into IL-6 dependent cells, the
presence of the L-gp130 protein led to longterm and
stable cytokine-independent growth of the cells [59,
60]. Interestingly, when transfected into murine em-
bryonic stem cells, L-gp130, even in the absence of
leukemia inhibitory factor led to an upregulation of
the transcription factor Oct4 accompanied by a stable
and complete blockade of cellular differentiation .
It was concluded from these data that forced juxtapo-
sition of the transmembrane domains of gp130 and
consequently its cytoplasmic domains mediated by
the jun-leucine-zipper was sufficient for gp130 sig-
naling in the absence of extracellular stimulation. The
dimerization of gp130 found in the absence of recep-
tor stimulation [57, 58] apparently does not position
the transmembrane domains and cytoplasmic do-
mains of gp130 in a way that is sufficient to induce
gp130 signaling. Interestingly, in a different study it
had been observed that also the membrane bound
IL-6R on cells was dimeric although the function of
this dimerization so far remains unclear .
The sIL-6R/sgp130 buffer in the blood
Since all cells in the body express gp130 [9, 10],
theoretically, all cells can be activated by the
IL-6/sIL-6R complex. Since the cellular responses to
the IL-6/sIL-6R complex can be dramatic, ranging
from induction of hepatocyte proliferation to massive
increase in hematopoiesis [40, 43] there must be a
control mechanism to prevent IL-6 trans-signaling
under steady-state conditions. Apparently, the con-
centrations of IL-6, sIL-6R and sgp130 have to be
taken into account. In healthy subjects, IL-6 plasma
levels are barely detectable and range between 2-6
pg/ml . They are massively increased during in-
flammation and can reach levels of several µg/ml
under septic conditions . In patients with rheu-
matoid arthritis i.e. during chronic inflammatory
conditions, IL-6 levels of up to 150 ng/ml have been
described . In contrast, levels of sIL-6R are in the
range of 75 ng/ml  and sgp130 levels have been
found at around 250-400 ng/ml [32, 66]. Thus, under
steady state conditions, levels of sIL-6R and sgp130
are roughly 1000 times higher than IL-6 levels. Fur-
thermore, as mentioned, IL-6 levels can increase up to
1 million fold in severe conditions , whereas
sIL-6R and sgp130 levels have been reported to only
increase not more than 2-5 fold during inflammation
[67, 68]. These concentrations imply that IL-6, once
secreted, will bind to sIL-6R in the plasma and this
complex will associate with sgp130 and thereby be
neutralized. Only when IL-6 levels exceed the levels
of sIL-6R and sgp130, IL-6 can act systemically – as
seen under septic conditions . Under physiologic
conditions IL-6 is thought to act in a paracrine fashion
. As recently reported, the sgp130Fc protein under
conditions, when sIL-6R levels largely exceed levels of
IL-6, can also block IL-6 classic signaling because then
free IL-6 will bind to the excess of sIL-6R and this
complex will bind to and will be neutralized by
sgp130Fc . It should be noted, however, that these
calculations do not take into account the local cyto-
kine and soluble cytokine receptor levels at the site of
inflammation, which are largely unknown since they
are mostly not experimentally accessible  .
In two recent publications, it was shown that a
single nucleotide polymorphism in the IL-6R gene
changing glutamine 258 into alanine resulted in
higher serum concentrations of sIL-6R was connected
to a lower risk of coronary heart disease [71, 72]. In-
terestingly, this amino acid is positioned exactly at the
cleavage site of the human IL-6R . This effect of
this single nucleotide polymorphism was explained
with the loss of membrane bound IL-6R from
hepatocytes, monocytes, and macrophages and a
concomitant loss of IL-6 signaling in these cells .
An alternative explanation would be that an increase
in sIL-6R levels would increase the capacity of the
sIL-6R/sgp130 buffer in the blood and therefore lead
to reduced overall IL-6 activity . Recently, it was
shown that by specifically
trans-signaling with the sgp130Fc protein, we could
significantly reduce the extent of atherosclerosis in
hypercholesterolemic LDL receptor negative mice
IL-6 Trans-signaling is pro-inflammatory
With the sgp130Fc protein as a molecular tool it
was possible to discriminate between IL-6 classic
signaling and IL-6 trans-signaling not only in vitro but
also in vivo. In gp130 dependent mouse models of
human diseases, global IL-6 signaling could be
blocked by the use of anti-IL-6 or anti-IL-6R neutral-
izing antibodies. In a parallel experiment, IL-6
Int. J. Biol. Sci. 2012, 8
trans-signaling could be blocked with the help of the
sgp130Fc protein. These experiments allowed to de-
cide whether the gp130 driven disease model was
based on IL-6 classic signaling or IL-6 trans-signaling
[54, 55]. The sgp130Fc could be applied by injection of
the recombinant protein or was synthesized in vivo in
transgenic mice expressing the sgp130Fc from liver
cells. Using this approach, we could show that in
models of inflammation, of autoimmune diseases and
of inflammation associated cancer, blockade of IL-6
trans-signaling by sgp130Fc was sufficient to block
the inflammatory progress (Table 1). In the case of
mycobacterium tuberculosis infection, treatment of
the animals with sgp130Fc protein did not lead to an
increase of bacterial burden in lung, liver and spleen,
whereas treatment with neutralizing TNFα-antibodies
resulted in a 10-100 fold increase in mycobacterial
colony forming units in the respective organs .
In a recent study comparing the susceptibility of
IL-6-/- mice and wt mice in an inflammatory colon
cancer model (AOM/DSS), it was shown that IL-6-/-
mice exhibited less tumors but more inflammation
than wt mice . It turned out that IL-6-/- mice were
impaired in regenerating the irritated intestinal epi-
thelium. A similar protective effect of IL-6 had already
been noted in mice infected with Citrobacter rodentium
. From these experiments it was concluded that in
the intestine upon wounding, the regenerative activi-
ties of IL-6 are needed for wound healing  and that
this activity was most likely mediated via the mem-
brane bound IL-6R [69, 78]. In a recent study, we used
a standardized cecal ligation and puncture (CLP)
sepsis model, leading to the death of about 60% of the
animals . In this model, we could demonstrate that
global blockade with a neutralizing IL-6 antibody did
not lead to a significant increase in survival of the
animals. In contrast, when only IL-6 trans-signaling
was blocked with 0.5 mg/kg sgp130Fc, 100% of the
animals survived. Interestingly, CLP led an upregu-
lation of the acute phase protein serum amyloid A
(SAA). This SAA induction was inhibited by global
IL-6 blockade but was unaffected by treatment of the
mice with sgp130Fc . Likewise, apoptosis of intes-
tinal epithelial cells was detected in mice after CLP,
which was only slightly reduced after global IL-6
blockade but was completely blocked after treatment
with sgp130Fc . These results clearly showed a
benefit of the more specific blockade of IL-6
trans-signaling as compared to global IL-6 inhibition
by neutralizing antibodies.
We inferred from all these experiments, that IL-6
trans-signaling represents the pro-inflammatory part
of IL-6 biologic activities whereas IL-6 classic signal-
ing comprises the anti-inflammatory or regenerative
activities of IL-6 such as regeneration of intestinal
epithelial cells , inhibition of epithelial apoptosis
and the activation of the hepatic acute phase response
. Since shedding of the IL-6R is mainly governed
by the protease ADAM17 [14, 80], we speculate that
ADAM17 has a decisive role in inflammation and
cancer  (Fig. 4).
Viral IL-6 as an example of pathophysio-
The genome of Human Herpesvirus 8 (HHV8)
also called Kaposi's sarcoma-associated herpesvirus
codes for a viral form of IL-6, designated vIL-6 .
Although this viral homolog shares only 25% se-
quence identity with human IL-6 it could be demon-
strated that it stimulates cells in a gp130 dependent
manner . Interestingly, it could be shown that
vIL-6 directly bound to gp130 without the need of
soluble of membrane bound IL-6R and that associa-
tion with gp130 was
STAT3-dependent proliferation of cells [83, 84]. This
was confirmed by the structure of vIL-6 bound to the
extracellular portion of gp130  and by the defini-
tion of the amino acid sequences responsible for the
ability of vIL-6 to directly bind to and activate gp130
. In addition, it could be shown that vIL-6 not only
stimulated cells from the outside but could also act
from within the cell [87, 88], which might be im-
portant for the pathophysiologic role of vIL-6 and
needs to be considered when strategies of vIL-6 neu-
tralization are assessed [87, 88].
sufficient to induce
Table 1. Efficacy of sgp130Fc in animal models of human diseases.
DSS-colitis, SAMP/YIT mouse model
Antigen induced arthritis, collagen induced arthritis
Air pouch model
Cecal ligation and puncture sepsis, LPS-mediated septic shock
Hypercholesterolemic LDL-receptor negative mice
Late-phase murine asthma model after OVA sensitization
AOM/DSS model, DSS only model
Xenograft model of human ovarian cancer cells in NOD/SCID mice
Pancreatic cancer caused by expression of oncogenic G12D K-ras
[8, 34, 64]
Int. J. Biol. Sci. 2012, 8
Fig. 4. Pro- and anti-inflammatory activities of IL-6. Anti-inflammatory activities of IL-6 include STAT3 dependent regeneration of
epithelial cells and the induction of the hepatic acute phase response. These activities are dependent on the membrane bound IL-6R.
Pro-inflammatory activities of IL-6 include recruitment of inflammatory cells, inhibition of apoptosis of inflammatory cells and inhibition of
regulatory T-cell differentiation.
Since vIL-6 is the only known cytokine, which
can stimulate gp130 without the help of an additional
receptor protein, we speculated that vIL-6 was a nat-
ural model for IL-6 trans-signaling [89-91]. Indeed, it
could be shown that vIL-6 affects neutrophil infiltra-
tion during acute inflammation in a similar way as the
IL-6/sIL-6R complex . Furthermore, in mice
transgenic for vIL-6 we observed development of a
phenotype, which closely resembled multicentric
Castleman disease . Interestingly, when we
crossed the vIL-6 transgenic mice with IL-6-/- mice,
the phenotype disappeared, indicating that vIL-6 col-
laborated with murine IL-6 in the development of the
pathophysiology . This might be very relevant for
the situation in patients because HHV8 has been as-
sociated with multicentric Castleman disease and
100% of HIV positive patients and 50% of HIV nega-
tive patients harbor the virus . Since IL-6R neu-
tralizing antibodies are already in the clinic for the
treatment of autoimmune diseases, neutralization of
human IL-6 should be considered for the treatment of
multicentric Castleman disease. Indeed, it was al-
ready noted in a clinical trial with IL-6R neutralizing
antibodies that patients with multicentric Castleman
disease, who were HHV8 positive, improved upon
neutralization of human IL-6 activity .
Consequences for the therapeutic targeting
Activities of IL-6 can be regenerative and pro-
tective during infection and inflammation [76, 77, 96].
On the other hand, IL-6 is needed for the activation of
the immune system (Fig. 4). Indeed it has been shown
that neutralization of IL-6 by an anti-IL-6R antibody
has beneficial effects in several autoimmune diseases
such as Rheumatoid Arthritis, Castleman's disease
and juvenile idiopathic arthritis and has been ap-
proved for treatment of these diseases . In clinical
trials, the benefit from blocking IL-6R activity for the
Int. J. Biol. Sci. 2012, 8
patients was at least as high as the benefit from
blocking TNFα activity. Autoimmune diseases are not
cured by anti-cytokine therapy but only suppressed.
Therefore, patients will likely have to be treated for
the rest of their lives. Therefore, side effects will be an
important issue of consideration for such therapies in
The principle of cytokine blockade differs be-
tween neutralizing antibodies and soluble receptor
binding proteins. The anti-human IL-6R antibody
tocilizumab blocks both, IL-6 classic signaling and
IL-6 trans-signaling (Fig. 1) and therefore blocks both,
pro- and anti-inflammatory activities of IL-6 (Fig. 4).
The IL-6 trans-signaling inhibitor sgp130Fc, however,
binds only IL-6 molecules, which are bound by the
sIL-6R (Fig. 5). Since during inflammatory states IL-6
concentrations at the site of inflammation are likely to
largely exceed concentrations of sIL-6R, many IL-6
molecules are not blocked and can induce regenera-
tion of intestine epithelial cells or induce the hepatic
acute phase reaction and thereby support the innate
immune response of the body in defense of bacterial
infection. Therefore we are looking forward to the
first clinical trials with sgp130Fc, which are planned
in early 2013.
Fig. 5. Consequences of specific IL-6 trans-signaling blockade by sgp130Fc. The sgp130Fc protein only binds to IL-6 molecules,
which are complexed with sIL-6R. Therefore, in the presence of an excess of IL-6, not all IL-6 molecules are neutralized and can induce
regeneration of epithelial cells or trigger the hepatic acute phase response.
The work of SRJ was funded by the Deutsche
Forschungsgemeinschaft, Bonn (SFB654, Project C5;
SFB841, project C1; SFB877, project A1) and by the
Cluster of Excellence ‘Inflammation at Interfaces’.
Dr. Rose-John is an inventor on patents describ-
ing the function of sgp130Fc. He is also a shareholder
of the CONARIS Research Institute (Kiel, Germany),
which is commercially developing sgp130Fc proteins
as therapeutics for inflammatory diseases.
1. Hirano T, Yasukawa K, Harada H, Taga T, Watanabe Y, Matsuda T, et al.
Complementary DNA for a novel human interleukin (BSF-2) that
induces B lymphocytes to produce immunoglobulin. Nature. 1986; 324:
Bazan JF. Haemopoietic receptors and helical cytokines. Immunol
Today. 1990; 11: 350-4.
Yamasaki K, Taga T, Hirata Y, Yawata H, Kawanishi Y, Seed B, et al.
Cloning and expression of the human interleukin-6 (BSF-2/IFN beta 2)
receptor. Science. 1988; 241: 825-8.
Hibi M, Murakami M, Saito M, Hirano T, Taga T, Kishimoto T.
Molecular cloning and expression of an IL-6 signal transducer, gp130.
Cell. 1990; 63: 1149-57.
Heinrich PC, Behrmann I, Haan S, Hermanns HM, Muller-Newen G,
Schaper F. Principles of interleukin (IL)-6-type cytokine signalling and
its regulation. Biochem J. 2003; 374: 1-20.
Scheller J, Grötzinger J, Rose-John S. Updating IL-6 classic- and
trans-signaling. Signal Transduction. 2006; 6: 240-59.
Ernst M, Jenkins BJ. Acquiring signalling specificity from the cytokine
receptor gp130. Trends Genet. 2004; 20: 23-32.
Nowell MA, Williams AS, Carty SA, Scheller J, Hayes AJ, Jones GW, et
al. Therapeutic targeting of IL-6 trans-signaling counteracts STAT3
control of the inflammatory infiltrate in experimental arthritis. J
Immunol. 2009; 182: 613-22.
Jones SA, Scheller J, Rose-John S. Therapeutic strategies for the clinical
blockade of IL-6/gp130 signaling. J Clin Invest. 2011; 121: 3375-83.
Int. J. Biol. Sci. 2012, 8
10. Kishimoto T. Interleukin-6: from basic science to medicine--40 years in
immunology. Annu Rev Immunol 2005; 23: 1-21.
11. Jostock T, Müllberg J, Özbek S, Atreya R, Blinn G, Voltz N, et al. Soluble
gp130 is the natural inhibitor of soluble IL-6R transsignaling responses.
Eur J Biochem. 2001; 268: 160-7.
12. Fischer M, Goldschmitt J, Peschel C, Kallen KJ, Brakenhoff JPJ, Wollmer
A, et al. A designer cytokine with high activity on human hematopoietic
progenitor cells. Nat Biotech. 1997; 15: 142-5.
13. Novick D, Engelmann H, Wallach D, Rubinstein M. Soluble cytokine
receptors are present in normal human urine. J Exp Med. 1989; 170:
14. Müllberg J, Schooltink H, Stoyan T, Gunther M, Graeve L, Buse G, et al.
The soluble interleukin-6 receptor is generated by shedding. Eur J
Immunol. 1993; 23: 473-80.
15. Lust JA, Donovan KA, Kline MP, Greipp PR, Kyle RA, Maihle NJ.
Isolation of an mRNA encoding a soluble form of the human
interleukin-6 receptor. Cytokine. 1992; 4: 96-100.
16. Dimitrov S, Lange T, Benedict C, Scheller J, Rose-John S, Jones S, et al.
Sleep Enhances IL-6 Trans-Signaling in Humans. Faseb J. 2006; 20:
17. Scheller J, Chalaris A, Garbers C, Rose-John S. ADAM17: a molecular
switch of inflammatory and regenerative responses? Trends Immunol.
2011; 32: 380-387.
18. Rose-John S, Heinrich PC. Soluble receptors for cytokines and growth
factors: generation and biological function. Biochem J. 1994; 300: 281-90.
19. Taga T, Hibi M, Hirata Y, Yamasaki K, Yasukawa K, Matsuda T, et al.
Interleukin-6 triggers the association of its receptor with a possible signal
transducer, gp130. Cell. 1989; 58: 573-81.
20. Müllberg J, Schooltink H, Stoyan T, Heinrich PC, Rose-John S. Protein
kinase C activity is rate limiting for shedding of the interleukin-6
receptor. Biochem Biophys Res Commun. 1992; 189: 794-800.
21. Müllberg J, Oberthur W, Lottspeich F, Mehl E, Dittrich E, Graeve L, et al.
The soluble human IL-6 receptor. Mutational characterization of the
proteolytic cleavage site. J Immunol. 1994; 152: 4958-68.
22. Jones SA, Novick D, Horiuchi S, Yamamoto N, Szalai AJ, Fuller GM.
C-reactive protein: a physiological activator of interleukin 6 receptor
shedding. J Exp Med. 1999; 189: 599-604.
23. Walev I, Vollmer P, Palmer M, Bhakdi S, Rose-John S. Pore-forming
toxins trigger shedding of receptors for interleukin 6 and
lipopolysaccharide. Proc Natl Acad Sci USA. 1996; 93: 7882-7.
24. Matthews V, Schuster B, Schütze S, Kallen K-J, Rose-John S. Cholesterol
depletion of the plasma membrane triggers shedding of the human
interleukin-6 receptor by TACE and independently of PKC. J Biol Chem.
2003; 278: 38829-39.
25. Vollmer P, Walev I, Rose-John S, Bhakdi S. Novel pathogenic mechanism
of microbial metalloproteinases: liberation of membrane-anchored
molecules in biologically active form exemplified by studies with the
human interleukin-6 receptor. Infect Immun. 1996; 64: 3646-51.
26. Chalaris A, Rabe B, Paliga K, Lange H, Laskay T, Fielding CA, et al.
Apoptosis is a natural stimulus of IL6R shedding and contributes to the
pro-inflammatory trans-signaling function of neutrophils. Blood. 2007;
27. DeLeo FR. Attractive shedding. Blood. 2007; 110: 1711-2.
28. Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, et al.
Reciprocal developmental pathways for the generation of pathogenic
effector TH17 and regulatory T cells. Nature. 2006; 441: 235-8.
29. Dominitzki S, Fantini MC, Neufert C, Nikolaev A, Galle PR, Scheller J, et
al. Cutting edge: trans-signaling via the soluble IL-6R abrogates the
induction of FoxP3 in naive CD4+CD25 T cells. J Immunol. 2007; 179:
30. Briso EM, Dienz O, Rincon M. Cutting Edge: Soluble IL-6R Is Produced
by IL-6R Ectodomain Shedding in Activated CD4 T Cells. J Immunol.
2008; 180: 7102-6.
31. Jones GW, McLoughlin RM, Hammond VJ, Parker CR, Williams JD,
Malhotra R, 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. 2010; 184: 2130-9.
32. Narazaki M, Yasukawa K, Saito T, Ohsugi Y, Fukui H, Koishihara Y, et
al. Soluble forms of the interleukin-6 signal-transducing receptor
component gp130 in human serum possessing a potential to inhibit
signals through membrane-anchored gp130. Blood. 1993; 82: 1120-6.
33. Zhang JG, Zhang Y, Owczarek CM, Ward LD, Moritz RL, Simpson RJ, et
al. Identification and characterization of two distinct truncated forms of
gp130 and a soluble form of leukemia inhibitory factor receptor
alpha-chain in normal human urine and plasma. J Biol Chem. 1998; 273:
34. Richards PJ, Nowell MA, Horiuchi S, McLoughlin RM, Fielding CA,
Grau S, et al. Functional characterization of a soluble gp130 isoform and
its therapeutic capacity in an experimental model of inflammatory
arthritis. Arthr Rheumat. 2006; 54: 1662-72.
35. Müllberg J, Dittrich E, Graeve L, Gerhartz C, Yasukawa K, Taga T, et al.
Differential shedding of the two subunits of the interleukin-6 receptor.
FEBS Lett. 1993; 332: 174-8.
36. Diamant M, Hansen MB, Rieneck K, Svenson M, Yasukawa K, Bendtzen
K. Differential interleukin-6 (IL-6) responses of three established
myeloma cell lines in the presence of soluble human IL-6 receptors. Leuk
Res. 1996; 20: 291-301.
37. Peters M, Jacobs S, Ehlers M, Vollmer P, Müllberg J, Wolf E, et al. The
function of the soluble interleukin 6 (IL-6) receptor in vivo: sensitization
of human soluble IL-6 receptor transgenic mice towards IL-6 and
prolongation of the plasma half-life of IL-6. J Exp Med. 1996; 183:
38. van Dam M, Müllberg J, Schooltink H, Stoyan T, Brakenhoff JP, Graeve
L, et al. Structure-function analysis of interleukin-6 utilizing
human/murine chimeric molecules. Involvement of two separate
domains in receptor binding. J Biol Chem. 1993; 268: 15285-90.
39. Fattori E, Della Rocca C, Costa P, Giorgio M, Dente B, Pozzi L, et al.
Development of progressive kidney damage and myeloma kidney in
interleukin-6 transgenic mice. Blood. 1994; 83: 2570-9.
40. Peters M, Schirmacher P, Goldschmitt J, Odenthal M, Peschel C, Dienes
HP, et al. Extramedullary expansion of hematopoietic progenitor cells in
IL-6/sIL-6R double transgenic mice. J Exp Med. 1997; 185: 755-66.
41. Schirmacher P, Peters M, Ciliberto G, Fattori E, Lotz J, Meyer zum
Büschenfelde KH, et al. Hepatocellular Hyperplasia, Plasmacytoma
Formation, and Extracellular
(IL)-6/Soluble IL-6 Receptor Double-Transgenic Mice. Am J Pathol. 1998;
42. Maione D, Di Carlo E, Li W, Musiani P, Modesti A, Peters M, et al.
Coexpression of IL-6 and soluble IL-6R causes nodular regenerative
hyperplasia and adenomas of the liver. Embo J. 1998; 17: 5588-97.
43. Peters M, Müller A, Rose-John S. Interleukin-6 and soluble Interleukin-6
Receptor: Direct Stimulation of gp130 and Hematopoiesis. Blood. 1998;
44. Dittrich E, Rose-John S, Gerhartz C, Mullberg J, Stoyan T, Yasukawa K, et
al. Identification of a region within the cytoplasmic domain of the
interleukin-6 (IL-6) signal transducer
ligand-induced endocytosis of the IL-6 receptor. J Biol Chem. 1994; 269:
45. Peters M, Blinn G, Solem F, Fischer M, Meyer zum Büschenfelde K-H,
Rose-John S. In Vivo and in vitro Activity of the gp130 Stimulating
Designer Cytokine Hyper-IL-6. J Immunol. 1998; 161: 3575-81.
46. Rose-John S, Schooltink H, Lenz D, Hipp E, Dufhues G, Schmitz H, et al.
Studies on the structure and regulation of the human hepatic
interleukin-6 receptor. Eur J Biochem. 1990; 190: 79-83.
47. Audet J, Miller CL, Rose-John S, Piret JM, Eaves CJ. Distinct role of gp130
activation in promoting self-renewal divisions by mitogenically
stimulated murine hematopoietic cells. Proc Natl Acad Sci USA. 2001; 98:
48. März P, Cheng J-C, Gadient RA, Patterson P, Stoyan T, Otten U, et al.
Sympathetic Neurons can produce and respond to Interleukin-6. Proc
Natl Acad Sci USA. 1998; 95: 3251-6.
49. März P, Heese K, Dimitriades-Schmutz B, Rose-John S, Otten U. Role of
Interleukin-6 and soluble IL-6 Receptor in Region Specific Induction of
Astrocytic Differentiation and Neurotrophin Expression. Glia. 1999; 26:
50. Klouche M, Bhakdi S, Hemmes M, Rose-John S. Novel Path of activation
of primary human smooth muscle cells: upregulation of gp130 creates an
autocrine activation loop by IL-6 and its soluble receptor. J Immunol.
1999; 163: 4583-9.
51. Viswanathan S, Benatar T, Rose-John S, Lauffenburger DA, Zandstra
PW. Ligand/receptor signaling threshold (LIST) model accounts for
gp130-mediated embryonic stem cell self-renewal responses to LIF and
HIL-6. Stem cells (Dayton, Ohio). 2002; 20: 119-38.
52. Humphrey RK, Beattie GM, Lopez AD, Bucay N, King CC, Firpo M, et al.
Maintenance of pluripotency in human embryonic stem cells is Stat3
independent. Stem cells (Dayton, Ohio). 2004; 22: 522-30.
53. Rose-John S, Scheller J, Elson G, Jones S. Interleukin-6 Biology is
Coordinated by Membrane-Bound and Soluble Receptors: Role in
Inflammation and Cancer. J Leuk Biol. 2006; 80: 227-36.
54. Rose-John S, Waetzig GH, Scheller J, Grotzinger J, Seegert D. The
IL-6/sIL-6R complex as a novel target for therapeutic approaches. Expert
Opin Ther Targets. 2007; 11: 613-24.
Hematopoiesis in Interleukin
gp130 important for
Int. J. Biol. Sci. 2012, 8
55. Waetzig GH, Rose-John S. Hitting a complex target: an update on
interleukin-6 trans-signalling. Expert Opin Ther Targets. 2012; 16: 225-36.
56. Scheller J, Schuster B, Holscher C, Yoshimoto T, Rose-John S. No
inhibition of IL-27 signaling by soluble gp130. Biochem Biophys Res
Commun. 2005; 326: 724-8.
57. Giese B, Roderburg C, Sommerauer M, Wortmann SB, Metz S, Heinrich
PC, et al. Dimerization of the cytokine receptors gp130 and LIFR
analysed in single cells. Journal of cell science. 2005; 118: 5129-40.
58. Tenhumberg S, Schuster B, Zhu L, Kovaleva M, Scheller J, Kallen KJ, et
al. gp130 Dimerization in the Absence of Ligand: preformed Cytokine
Receptor Complexes. Biochem Biophys Res Commun. 2006; 346: 649-57.
59. Stuhlmann-Laeisz C, Lang S, Chalaris A, Paliga K, Sudarman E, Eichler J,
et al. Forced dimerization of gp130 leads to constitutive STAT3
activation, cytokine independent growth and blockade of differentiation
of embryonic stem cells. Mol Biol Cell. 2006; 17: 2986-95.
60. Suthaus J, Tillmann A, Lorenzen I, Bulanova E, Rose-John S, Scheller J.
Forced homo- and heterodimerization of all gp130-type receptor
complexes leads to constitutive ligand-independent signaling and
cytokine-independent growth. Mol Biol Cell. 2010; 21: 2797-807.
61. Schuster B, Meinert W, Rose-John S, Kallen K-J. The human interleukin–6
(IL-6) receptor exists as a preformed dimer in the plasma membrane.
FEBS Lett. 2003; 538: 113-6.
62. Scambia G, Testa U, Panici PB, Martucci R, Foti E, Petrini M, et al.
Interleukin-6 serum levels in patients with gynecological tumors. Int J
Cancer. 1994; 57: 318-23.
63. Waage A, Brandtzaeg P, Halstensen A, Kierulf P, Espevik T. The
complex pattern of cytokines in serum from patients with meningococcal
septic shock. J Exp Med. 1989; 169: 333-8.
64. Nowell MA, Richards PJ, Horiuchi S, Yamamoto N, Rose-John S, Topley
N, et al. Soluble IL-6 Receptor Governs IL-6 Activity in Experimental
Arthritis: Blockade of Arthritis Severity by Soluble Glycoprotein 130. J
Immunol. 2003; 171: 3202–9.
65. Honda M, Yamamoto S, Cheng M, Yasukawa K, Suzuki H, Saito T, et al.
Human soluble IL-6 receptor: its detection and enhanced release by HIV
infection. J Immunol. 1992; 148: 2175-80.
66. Padberg F, Feneberg W, Schmidt S, Schwarz MJ, Korschenhausen D,
Greenberg BD, et al. CSF and serum levels of soluble interleukin-6
receptors (sIL-6R and sgp130), but not of interleukin-6 are altered in
multiple sclerosis. J Neuroimmunol. 1999; 99: 218-23.
67. Doganci A, Eigenbrod T, Krug N, De Sanctis GT, Hausding M,
Erpenbeck VJ, et al. The IL-6R alpha chain controls lung
CD4+CD4+CD25+T regulatory cell development and function during
allergic airway inflammation in vivo. J Clin Invest. 2005; 115: 313 –25.
68. Schuett H, Oestreich R, Waetzig GH, Annema W, Luchtefeld M, Hillmer
A, et al. Transsignaling of interleukin-6 crucially contributes to
atherosclerosis in mice. Arterioscler Thromb Vasc Biol. 2012; 32: 281-90.
69. Scheller J, Chalaris A, Schmidt-Arras D, Rose-John S. The pro- and
anti-inflammatory properties of the cytokine interleukin-6. Biochim
Biophys Acta. 2011; 1813: 878-88.
70. Garbers C, Thaiss W, Jones GW, Waetzig GH, Lorenzen I, Guilhot F, et
al. Inhibition of classic signaling is a novel function of soluble
glycoprotein 130 (sgp130), which is controlled by the ratio of interleukin
6 and soluble interleukin 6 receptor. J Biol Chem. 2011; 286: 42959-70.
71. Sarwar N, Butterworth AS, Freitag DF, Gregson J, Willeit P, Gorman DN,
et al. Interleukin-6 receptor pathways in coronary heart disease: a
collaborative meta-analysis of 82 studies. Lancet. 2012; 379: 1205-13.
72. Hingorani AD, Casas JP. The interleukin-6 receptor as a target for
prevention of coronary heart disease: a mendelian randomisation
analysis. Lancet. 2012; 379: 1214-24.
73. Boekholdt SM, Stroes ES. The interleukin-6 pathway and atherosclerosis.
Lancet. 2012; 379: 1176-8.
74. Scheller J, Rose-John S. The interleukin 6 pathway and atherosclerosis.
Lancet. 2012; 380: 338.
75. Sodenkamp J, Waetzig GH, Scheller J, Seegert D, Grotzinger J, Rose-John
S, et al. Therapeutic targeting of interleukin-6 trans-signaling does not
affect the outcome of experimental tuberculosis. Immunobiology. 2012,
76. Grivennikov S, Karin E, Terzic J, Mucida D, Yu G-Y, Vallabhapurapu S,
et al. IL-6 and STAT3 signaling is required for survival of intestinal
epithelial cells and colitis associated cancer. Cancer Cell. 2009; 16: 103-13.
77. Dann SM, Spehlmann ME, Hammond DC, Iimura M, Hase K, Choi LJ, et
al. IL-6-dependent mucosal protection prevents establishment of a
microbial niche for attaching/effacing lesion-forming enteric bacterial
pathogens. J Immunol. 2008; 180: 6816-26.
78. Becker C, Fantini MC, Schramm C, Lehr HA, Wirtz S, Nikolaev A, et al.
TGF-beta suppresses tumor progression in colon cancer by inhibition of
IL-6 trans-signaling. Immunity. 2004; 21: 491-501.
79. Barkhausen T, Tschernig T, Rosenstiel P, van Griensven M, Vonberg RP,
Dorsch M, et al. Selective blockade of interleukin-6 trans-signaling
improves survival in a murine polymicrobial sepsis model. Crit Care
Med. 2011; 39: 1407-13.
80. Chalaris A, Gewiese J, Paliga K, Fleig L, Schneede A, Krieger K, et al.
ADAM17-mediated shedding of the IL6R induces cleavage of the
membrane stub by gamma-secretase. Biochim Biophys Acta. 2010; 1803:
81. Neipel F, Albrecht JC, Ensser A, Huang YQ, Li JJ, Friedman Kien AE, et
al. Human herpesvirus 8 encodes a homolog of interleukin-6. J Virol.
1997; 71: 839-42.
82. Molden J, Chang Y, You Y, Moore PS, Goldsmith MA. A Kaposi`s
Sarcoma-associated Herpesvirus-encoded Cytokine Homolog (vIL-6)
Activates Signaling through the Shared gp130 Receptor Subunit. J Biol
Chem. 1997; 272: 19625-31.
83. Müllberg J, Geib T, Jostock T, Hoischen SH, Vollmer P, Voltz N, et al.
IL-6-Receptor Independent Stimulation of Human gp130 by Viral IL-6. J
Immunol. 2000; 164: 4672-7.
84. Hoischen SH, Vollmer P, Marz P, Ozbek S, Gotze KS, Peschel C, et al.
Human herpes virus 8 interleukin-6 homologue triggers gp130 on
neuronal and hematopoietic cells. Eur J Biochem / FEBS J. 2000; 267:
85. Chow D, He X, Snow AL, Rose-John S, Garcia KC. Structure of an
extracellular gp130 cytokine receptor signaling complex. Science. 2001;
86. Adam N, Rabe B, Suthaus J, Grotzinger J, Rose-John S, Scheller J.
Unraveling viral interleukin-6 binding to gp130 and activation of
STAT-signaling pathways independently of the interleukin-6 receptor. J
Virol. 2009; 83: 5117-26.
87. Kovaleva M, Bussmeyer I, Rabe B, Grotzinger J, Sudarman E, Eichler J, et
al. Abrogation of viral interleukin-6 (vIL-6)-induced signaling by
intracellular retention and neutralization of vIL-6 with an anti-vIL-6
single-chain antibody selected by phage display. J Virol. 2006; 80:
88. Meads MB, Medveczky PG.
herpesvirus-encoded viral interleukin-6 is secreted and modified
differently than human interleukin-6: evidence for a unique autocrine
signaling mechanism. J Biol Chem. 2004; 279: 51793-803.
89. Klouche M, Brockmeyer N, Knabbe C, Rose-John S. Human herpesvirus
8-derived viral IL-6 induces PTX3 expression in Kaposi's sarcoma cells.
Aids. 2002; 16: F9-18.
90. Klouche M, Carruba G, Castagnetta L, Rose-John S. Virokines in the
pathogenesis of cancer: focus on human herpesvirus 8. Ann N Y Acad
Sci. 2004; 1028: 329-39.
91. Suthaus J, Adam N, Grotzinger J, Scheller J, Rose-John S. Viral
Interleukin-6: Structure, pathophysiology
neutralization. Eur J Cell Biol. 2011; 90: 495-504.
92. Fielding CA, McLoughlin RM, Colmont CS, Kovaleva M, Harris DA,
Rose-John S, et al. Viral IL-6 blocks neutrophil infiltration during acute
inflammation. J Immunol. 2005; 175: 4024-9.
93. Suthaus J, Stuhlmann-Laeisz C, Tompkins VS, Rosean TR, Klapper W,
Tosato G, et al. HHV-8-encoded viral IL-6 collaborates with mouse IL-6
in the development of multicentric Castleman disease in mice. Blood.
2012; 119: 5173-81.
94. Soulier J, Grollet L, Oksenhendler E, Cacoub P, Cazals Hatem D, Babinet
P, et al. Kaposi's sarcoma-associated herpesvirus-like DNA sequences in
multicentric Castleman's disease. Blood. 1995; 86: 1276-80.
95. Nishimoto N, Kanakura Y, Aozasa K, Johkoh T, Nakamura M, Nakano S,
et al. Humanized anti-interleukin-6 receptor antibody treatment of
multicentric Castleman disease. Blood. 2005; 106: 2627-3.
96. Bollrath J, Phesse TJ, von Burstin VA, Putoczki T, Bennecke M, Bateman
T, et al. gp130-mediated Stat3 activation in enterocytes regulates cell
survival and cell-cycle progression
tumorigenesis. Cancer Cell. 2009; 15: 91-102.
97. Tanaka T, Narazaki M, Kishimoto T. Therapeutic Targeting of the
Interleukin-6 Receptor. Annu Rev Pharmacol Toxicol. 2012; 52: 199-219.
98. Atreya R, Mudter J, Finotto S, Müllberg J, Jostock T, Wirtz S, et al.
Blockade of IL-6 transsignaling abrogates established experimental
colitis in mice by suppression of the antiapoptotic resistance of lamina
propria T cells. Nat Med. 2000; 6: 583-8.
99. Mitsuyama K, Matsumoto S, Rose-John S, Suzuki A, Hara T, Tomiyasu
N, et al. STAT3 activation via interleukin 6 trans-signalling contributes to
ileitis in SAMP1/Yit mice. Gut. 2006; 55: 1263-9.
100. Rabe B, Chalaris A, May U, Waetzig GH, Seegert D, Williams AS, et al.
Transgenic blockade of interleukin 6 transsignaling abrogates
inflammation. Blood. 2008; 111: 1021-8.
and strategies of
Int. J. Biol. Sci. 2012, 8
101. Greenhill CJ, Rose-John S, Lissilaa R, Ferlin W, Ernst M, Hertzog PJ, et al.
IL-6 trans-signaling modulates
responses via STAT3. Journal of immunology. 2011; 186: 1199-208.
102. Finotto S, Eigenbrod T, Karwot R, Boross I, Doganci A, Ito H, et al. Local
blockade of IL-6R signaling induces lung CD4+ T cell apoptosis in a
murine model of asthma via regulatory T cells. Int Immunol. 2007; 19:
103. Matsumoto S, Hara T, Mitsuyama K, Yamamoto M, Tsuruta O, Sata M, et
al. Essential roles of IL-6 trans-signaling in colonic epithelial cells,
induced by the IL-6/soluble-IL-6 receptor derived from lamina propria
macrophages, on the development of colitis-associated premalignant
cancer in a murine model. J Immunol. 2010; 184: 1543-51.
104. Lo CW, Chen MW, Hsiao M, Wang S, Chen CA, Hsiao SM, et al. IL-6
trans-signaling in formation and progression of malignant ascites in
ovarian cancer. Cancer Res. 2011; 71: 424-34.
105. Lesina M, Kurkowski MU, Ludes K, Rose-John S, Treiber M, Klöppel G,
et al. Stat3/Socs3 activation by IL-6 transsignaling promotes progression
of pancreatic intraepithelial neoplasia and development of pancreatic
cancer. Cancer Cell. 2011; 19: 456-69.