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Clinical Science (2012) 122, 143–159 (Printed in Great Britain) doi:10.1042/CS20110340
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IL-6/IL-6 receptor system and its role in
physiological and pathological conditions
Masahiko MIHARA, Misato HASHIZUME, Hiroto YOSHIDA, Miho SUZUKI and
Masashi SHIINA
Fuji-Gotemba Research Laboratories, Product Research Department, Chugai Pharmaceutical Co. Ltd., Gotemba, 412-8513,
Japan
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IL (interleukin)-6, which was originally identified as a B-cell differentiation factor, is a multifunctional
cytokine that regulates the immune response, haemopoiesis, the acute phase response and
inflammation. IL-6 is produced by various types of cell and influences various cell types,
and has multiple biological activities through its unique receptor system. IL-6 exerts its biological
activities through two molecules: IL-6R (IL-6 receptor) and gp130. When IL-6 binds to mIL6R (membrane-bound form of IL-6R), homodimerization of gp130 is induced and a high-affinity
functional receptor complex of IL-6, IL-6R and gp130 is formed. Interestingly, sIL-6R (soluble form
of IL-6R) also binds with IL-6, and the IL-6–sIL-6R complex can then form a complex with gp130.
The homodimerization of receptor complex activates JAKs (Janus kinases) that then phosphorylate
tyrosine residues in the cytoplasmic domain of gp130. The gp130-mediated JAK activation
by IL-6 triggers two main signalling pathways: the gp130 Tyr759 -derived SHP-2 (Src homology
2 domain-containing protein tyrosine phosphatase-2)/ERK (extracellular-signal-regulated kinase)
MAPK (mitogen-activated protein kinase) pathway and the gp130 YXXQ-mediated JAK/STAT
(signal transducer and activator of transcription) pathway. Increased IL-6 levels are observed
in several human inflammatory diseases, such as rheumatoid arthritis, Castleman’s disease and
systemic juvenile idiopathic arthritis. IL-6 is also critically involved in experimentally induced
autoimmune diseases. All clinical findings and animal models suggest that IL-6 plays a number of
critical roles in the pathogenesis of autoimmune diseases. In the present review, we first summarize
the IL-6/IL-6R system and IL-6 signal transduction, and then go on to discuss the physiological and
pathological roles of IL-6.
Key words: autoimmune disease, bone metabolism, immune response, inflammation, interleukin-6 (IL-6) signalling.
Abbreviations: AA, amyloid A; ACD, anaemia of chronic disease; ADAM, a disintegrin and metalloproteinase; ADAMTS,
ADAM with thrombospondin motifs; α 1 -AGP, α 1 -acid glycoprotein; AMD, age-related macular degeneration; APP, acute-phase
protein; APR, acute-phase response; AR, androgen receptor; BSF, B-cell stimulatory factor; CAC, colitis-associated cancer; CCL,
CC chemokine ligand; CD62L, CD62 ligand; CNV, choroidal neovascularization; CRP, C-reactive protein; ERK, extracellularsignal-regulated kinase; FAS, fatty acid synthase; GM-CSF, granulocyte/macrophage colony-stimulating factor; HDL, high-density
lipoprotein; ICAM, intercellular adhesion molecule; IFN, interferon; IGF-1, insulin-like growth factor-1; IL, interleukin; IL-6R,
IL-6 receptor; JAK, Janus kinase; JIA, juvenile idiopathic arthritis; LPS, lipopolysaccharide; MAPK, mitogen-activated protein
kinase; MCP, monocyte chemoattractant protein; mgp130, membrane-bound gp130; mIL-6R, membrane-bound IL-6R; MM,
multiple myeloma; MMP, matrix metalloproteinase; PBEF, pre-B-cell colony-enhancing factor; PPAR, peroxisome-proliferatoractivated receptor; RA, rheumatoid arthritis; RA-FLS, fibroblast-like synoviocytes from RA patients; RANKL receptor activator
of nuclear factor κB ligand; ROR, retinoic acid-receptor-related orphan receptor; SAA, serum AA; sgp130, soluble gp130; SHP-2,
Src homology domain-containing protein tyrosine phosphatase-2; sIL-6R, soluble IL-6R; sJIA, systemic JIA; SOCS, suppressor
of cytokine signalling; SREBP, sterol-regulatory-element-binding protein; STAT, signal transducer and activator of transcription;
TAG, triacylglycerol; TCZ, tocilizumab; TGF, transforming growth factor; TNF, tumour necrosis factor; Treg, regulatory T-cell;
VEGF, vascular endothelial growth factor; VLDL, very-low-density lipoprotein.
Correspondence: Dr Masahiko Mihara (email [email protected]).
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INTRODUCTION
IL (interleukin)-6 was discovered in 1986 as a B-cell
differentiation factor that differentiates activated Bcells into immunoglobulin-producing cells [1]; it was
therefore named BSF (B-cell stimulatory factor)-2. It
was subsequently found to be identical with other factors
described as IFN (interferon)-β2 [2], 26 kDa protein
[3], hybridoma/plasmacytoma growth factor [4] and
hepatocyte-stimulating factor [4].
IL-6 is produced by various types of cell, such as
T-cells, B-cells, monocytes, fibroblasts, keratinocytes,
endothelial cells, mesangial cells, adipocytes and some
tumour cells. IL-6R (IL-6 receptor) is mainly expressed
in haemopoietic cells, such as T-cells, monocytes,
activated B-cells and neutrophils. Interestingly, IL-6
influences various cell types and has multiple biological
activities through its unique receptor systems. Elevated
production of IL-6 contributes to the pathogenesis of
various autoimmune and inflammatory diseases, and IL6 blockade by TCZ [tocilizumab; a humanized anti(human IL-6R) monoclonal antibody] has been proven
to improve symptoms of RA (rheumatoid arthritis),
Castleman’s disease and sJIA [systemic JIA (juvenile
idiopathic arthritis)] [5]. IL-6 is a growth factor for
certain tumours, such as MM (multiple myeloma) and
renal carcinoma cells. Moreover, IL-6 is suggested to
be involved in cancer cachexia. Cancer cachexia is a
metabolic state that is seen in several malignant disorders
and it is commonly recognized as progressive weight
loss with depletion of host reserves of adipose tissue and
skeletal muscle.
IL-6/IL-6R SYSTEM
IL-6 exerts its biological activities through two molecules:
IL-6R (also known as IL-6Rα, gp80 or CD126) and
gp130 (also referred to as IL-6Rβ or CD130) [6]. IL6R is important for ligand binding, but it only has 82
amino acids in its cytoplasmic domain, indicating that
it can play only a minor role in signal transduction.
However, the cytoplasmic tail of the IL-6R may play a
decisive role in basolateral sorting, which is an important
function in polarized epithelial cells [7]. In contrast, the
cytoplasmic domain of gp130 contains several potential
motifs for intracellular signalling, such as the YSTV
sequence for SHP-2 (Src homology domain-containing
protein tyrosine phosphatase-2) recruitment and YXXQ
motifs (where X is any amino acid) for STAT (signal
transducer and activator of transcription) activation.
gp130 does not have an intrinsic kinase domain; instead,
like other cytokine receptors, the cytoplasmic domain
of gp130 contains regions required for its association
with a non-receptor tyrosine kinase called JAK (Janus
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Figure 1 IL-6R system
kinase), through which downstream signalling cascades
are initiated.
When IL-6 binds to mIL-6R (membrane-bound IL6R), homodimerization of gp130 is induced, and a highaffinity functional receptor complex of IL-6, IL-6R and
gp130 is formed. sIL-6R (soluble IL-6R), which lacks
the intracytoplasmic portion of mIL-6R and is produced
either by the enzymatic cleavage of mIL-6R by ADAM
(a disintegrin and metalloproteinase)-17 or by alternative
splicing, can also bind with IL-6, and then the complex
of IL-6 and sIL-6R can form a complex with gp130
(Figure 1). This unique receptor signalling system is
termed IL-6 trans-signalling [8].
mgp130 (membrane-bound gp130) is expressed
ubiquitously in the body. Therefore the IL-6–sIL-6R
complex could, theoretically, stimulate most cells in
the body. However, this trans-signalling is thought to
be highly regulated by sgp130 (soluble gp130), which
exists in higher concentrations in circulating blood.
sgp130 binds to the IL-6–sIL-6R complex and thereby
inhibits the binding of the IL-6–sIL-6R complex to
mgp130 [9,10]. Thus sgp130 is a natural inhibitor of IL-6
signalling. IL-6 binds to IL-6R with an affinity of 10 − 9
to 10 − 10 mol/l and gp130 binds to IL-6–sIL-6R complex
with an affinity of 10 − 11 mol/l [6,11–13]. In fact, TCZ
can dissociate the IL-6–sIL-6R complex, but not the IL6–sIL-6R–sgp130 complex, suggesting that the IL-6–sIL6R complex is more rigid than the IL-6–sIL-6R–sgp130
complex [14].
gp130 is used in the signalling of many other members
of the IL-6 family of cytokines, including LIF (leukaemia
inhibitory factor), CNTF (ciliary neurotrophic factor),
OSM (oncostatin M), CT-1 (cardiotrophin-1), CLC
(cardiotrophin-like related cytokine), also known as
NNT-1 (novel neurotrophin-1) or BSF-3, NPN
(neuropoietin), IL-11 and IL-27 [15–17]. The sharing of
the gp130 molecule by other IL-6 superfamily cytokines
may explain their functional redundancy. A similar
system can also be seen within the other cytokine
IL-6 signalling and its biological activities
Figure 2 IL-6 signalling pathways
MEK, MAPK/ERK kinase.
families; for example, the group of cytokines comprising
IL-3, IL-5 and GM-CSF (granulocyte/macrophage
colony-stimulating factor) uses a common β receptor,
and the group of ILs including IL-2, IL-4, IL-7, IL-9,
IL-15 and IL-21 uses a common γ receptor component
[18].
The structure of the gp130–IL-6R–IL-6 complex has
been solved by X-ray crystallography: it is a hexamer
comprising two IL-6, two IL-6R and two gp130 proteins
[19]. It has been argued, however, that the signalling
complex is built of one IL-6–IL-6R complex bound to
two gp130 proteins [20].
IL-6 SIGNAL TRANSDUCTION
It is thought that receptor homodimerization brings the
JAKs into close proximity, resulting in their mutual
transactivation. The activated JAKs phosphorylate
tyrosine residues in the cytoplasmic domain of gp130.
There are six tyrosine residues in the human gp130
cytoplasmic domain. The gp130-mediated JAK activation
by IL-6 triggers two main signalling pathways: the
gp130 Tyr759 -derived SHP-2/ERK (extracellular-signalregulated kinase) MAPK (mitogen-activated protein
kinase) pathway and the gp130 YXXQ-mediated
JAK/STAT pathway (Figure 2) [21].
In the gp130 Tyr759 -derived SHP-2/ERK MAPK
pathway, upon IL-6 stimulation, SHP-2 is recruited
to the phosphorylated Tyr759 residue of gp130. After
being recruited, SHP-2 is phosphorylated by JAKs and
then interacts with Grb2 (growth-factor-receptor-bound
protein 2), which is constitutively associated with Sos
(son-of-sevenless), a GDT/GTP exchanger for Ras. The
GTP form of Ras transmits signals that lead to activation
of the ERK MAPK cascade, which activates transcription
factors such as NF-IL-6 [C/EBPβ (CCAAT/enhancerbinding protein β)] that can act through their own cognate
response elements in the genome.
In the gp130 YXXQ-mediated JAK/STAT pathway,
upon IL-6 stimulation, STAT proteins are recruited to
the phosphorylated YXXQ/YXPQ motifs and are then
phosphorylated by JAKs. The activated STAT proteins
form a heterodimer (STAT1–STAT3) or homodimers
(STAT1–STAT1 and/or STAT3–STAT3), subsequently
translocate to the nucleus and activate the transcription of
target genes. Interestingly, SOCS (suppressor of cytokine
signalling) is one of the target genes of the JAK/STAT
pathway. SOCS inhibits JAK activity and thus negatively
regulates the signals [22], suggesting the existence of an
autoregulatory mechanism for this signalling pathway.
These two signals independently induce a variety of
biological activities. For example, we have reported that
the SHP-2/ERK MAPK pathway induces MMP (matrix
metalloproteinase) production and the JAK/STAT
pathway induces RANKL (receptor activator of nuclear
factor κB ligand) expression in synovial cells [23,24].
PHYSIOLOGICAL AND PATHOLOGICAL
ROLES OF IL-6
Acute-phase response
The APR (acute-phase response) is rapidly induced by
inflammation associated with infection, injury and other
factors. This reaction neutralizes pathogens and prevents
their further invasion, and also minimizes tissue damage.
Briefly, the APR is involved in the body’s recovery
from an unwanted inflammatory state. The APR consists
of fever, an increase in vascular permeability and
the production of APPs (acute-phase proteins) by
hepatocytes.
Animal experiments have shown that central IL-6 is
necessary for the fever response: body temperature rose
significantly after intracerebroventricular injection of IL6 in rats; however, when administered intravenously or
intraperitoneally, IL-6 had no effect on body temperature
[25]. However, injection of recombinant human IL6 caused influenza-like symptoms, including fever in
human breast cancer and lung cancer patients [26].
Thermal stress promotes lymphocyte trafficking via the
enhanced expression of ICAM (intercellular adhesion
molecule)-1 and CCL (CC chemokine ligand) 21 in
endothelial cells. Interestingly, IL-6 trans-signalling
involves the thermal induction of ICAM-1 [27,28]. This
system is important during inflammation by augmenting
lymphocyte trafficking to inflamed tissues.
When human IL-6 (1–10 μg/kg of body weight
per day) was administered into humans by daily
subcutaneous injection for 7 days, increases were
observed in the positive APPs, such as SAA [serum
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transplantation or toxic injury. Liver regeneration leads
to hepatocyte and non-parenchymal cell proliferation.
IL-6-deficient mice had impaired liver regeneration
characterized by liver necrosis and failure. There was a
blunted DNA synthetic response in hepatocytes of these
mice, but not in non-parenchymal liver cells [40]. This fact
suggests that IL-6 is an important factor for homoeostasis
of the liver.
Angiogenesis
Figure 3 APR by IL-6
AA (amyloid A)], CRP (C-reactive protein), α 1 -AGP
(α 1 -acid glycoprotein), α 1 -antichymotrypsin, haptoglobin, α 1 -antitrypsin, fibrinogen, complement component C3 and caeruloplasmin, with the greatest incremental
changes and fastest responses being observed for CRP and
SAA. Negative APPs, such as transferrin, transthyretin
and retinol-binding protein, fell to a nadir within 48–96 h
after the first IL-6 injection [29]. With TCZ treatment
of patients with RA or other inflammatory diseases,
and in TCZ treatment of monkey arthritis, CRP levels
rapidly decreased and became negative, indicating that
IL-6 is the main inducer of CRP in primates [30–32]. In
a mouse study, the production of APPs (haptoglobin,
α 1 -AGP and SAA) was remarkably increased by the
injection of turpentine, Listeria monocytogenes or LPS
(lipopolysaccharide). In contrast, APP production by
turpentine and L. monocytogenes was not observed in
IL-6-deficient mice. In the case of LPS, APP production
was only slightly reduced compared with wild-type
mice. This result suggests that LPS systemically induces
inflammatory mediators other than IL-6 [33] (Figure 3).
AA amyloidosis is a severe complication of chronic
inflammatory diseases and chronic infections [34,35]. AA
amyloidosis is caused by the deposition of insoluble
fibrils containing AA protein, which is derived from its
precursor, SAA [36]. SAA is an APP that is synthesized
predominantly in the liver after stimulation by IL-6. SAA
circulates as an apolipoprotein to HDL (high-density
lipoprotein). When SAA is dissociated from HDL and
degraded, it is deposited as AA fibrils in the extracellular
space of vital tissues, leading to organ dysfunction such
as renal failure and gastrointestinal tract dysfunction.
Therefore it is thought that IL-6 blockade will be a useful
therapy for AA amyloidosis. In fact, IL-6 blockade has
been shown to dramatically ameliorate AA amyloidosis
in animal models and in patients with sJIA and RA [37–
39].
The liver has the ability to regenerate, allowing
for rapid recovery after partial hepatectomy, liver
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Angiogenesis is an essential component of inflammation and its resolution. Inflammatory cells, such as
monocytes/macrophages, T-cells and monocytes, fully
participate in the angiogenic process by secreting pro- and
anti-inflammatory cytokines that can control endothelial
cell proliferation, survival and apoptosis, as well as their
migration and activation. It is reported that a number
of growth factors and cytokines have angiogenic activity;
these include VEGF (vascular endothelial growth factor),
bFGF (basic fibroblast growth factor), EGF (epidermal
growth factor), TGF (transforming growth factor)-β, IL6, IL-8, IL-1 and TNF (tumour necrosis factor)-α.
In RA patients, changes in the synovium are marked
by neovascularization, infiltration of inflammatory cells
and synoviocyte hyperplasia, which together produce a
pannus (inflamed vascular tissue). Newly formed blood
vessels are thought to be involved in the development
and maintenance of synovitis because they support
the infiltration of inflammatory cells and the growth
and survival of synovial cells. Significant increases in
VEGF levels in RA patients correlate with disease
activity, suggesting that VEGF is implicated in RA
pathogenesis [41]. Treatment with TCZ significantly
lowers VEGF levels [42]. IL-6 induced tubule formation
in a co-culture system of HUVECs (human umbilical
venous endothelial cells) and RA-FLS (fibroblast-like
synoviocytes from RA patients), and this angiogenesis
was completely inhibited by an anti-VEGF antibody,
indicating that VEGF plays a crucial role in IL-6-induced
angiogenesis [43]. IL-6 induces VEGF production from
synovial cells [42,43], and semi-quantitative assessment
by ultrasonography indicated that TCZ significantly
decreases neovascularization in patients with RA [44].
AMD (age-related macular degeneration) is complicated by CNV (choroidal neovascularization), leading
to severe vision loss and blindness. CNV observed in
AMD develops with chronic inflammation adjacent to
the retinal pigment epithelium, Bruch’s membrane and
choriocapillaris. Studies have indicated that VEGF is a
critical factor for promoting CNV [45,46]. Interestingly,
increased serum levels of IL-6 and CRP have proven to
be correlated with the progression of AMD [47]. CNV
induction by laser treatment stimulated IL-6 expression
in the retinal pigment epithelium–choroid complex, and
blockade of IL-6 signalling led to a significant suppression
IL-6 signalling and its biological activities
of CNV [48]. These lines of evidence suggest that VEGF
induced by IL-6 plays a role in CNV.
Neutrophil trafficking
Under conditions of inflammation, neutrophils migrate
into the inflamed sites and the number of neutrophils in
the circulating blood is substantially increased.
IL-6 acts as a stimulus for myelopoiesis and causes
accompanying changes in the numbers of peripheral
neutrophils [49]. Briefly, an injection of IL-6 caused
biphasic neutrophilia with an initial peak at 1.5 h and
a second sustained wave of neutrophilia between 4 and
12 h. The bone marrow showed no significant changes
at 1.5 h, suggesting that the peripheral neutrophilia is
caused by demargination of intravascular neutrophils. On
the other hand, the bone marrow at 12 h showed a mild
myeloid hyperplasia of myeloblasts and promyelocytes.
Migrated neutrophils in inflamed sites are deeply
involved in the onset and maintenance of inflammation
through their robust production of inflammatory
mediators, such as prostaglandins, ROS (reactive oxygen
species), complements, proteases and cytokines. Many
investigations have shown that adhesion molecules and
chemokines are essential for neutrophil transmigration
[50]. IL-6 augments the expression of adhesion molecules
such as VCAM (vascular cell adhesion molecule)-1
and ICAM-1 in inflamed sites and endothelial cells, and
induces the production of chemokines such as
CXCL (CXC chemokine ligand) 8/IL-8, CCL2/MCP
(monocyte chemoattractant protein)-1, CCL8/MCP-3
and CCL20 from many kinds of cells [51–54]. In fact, IL6 blockade reduced transmigration of neutrophils into
inflamed site in arthritis and in the air pouch model
[32,55].
On the other hand, circulating neutrophils also
play an essential role in the course of inflammation,
because removal of neutrophils from circulating blood
ameliorates inflammation in RA and inflammatory bowel
disease patients [56–58]. One mechanism of neutrophilia
is thought to be the mobilization of neutrophils from the
marginal pool into the circulation. In the marginal pool,
leucocyte rolling and adhesion is mediated by the sequential interaction of adhesion molecules on the leucocyte
with counter-ligands on the vascular endothelium and
extra-vascular structures [59]. Once neutrophils are activated, the expression levels of CD162/PSGL (P-selectin
glycoprotein ligand)-1, CD62L (CD62 ligand)/L-selectin
and CD11b are changed, and neutrophils then translocate
from the marginal pool into the circulating blood. Suwa
et al. [60] reported that IL-6 injection decreased CD62L
expression on circulating neutrophils in rabbits. We also
found that IL-6 reduces CD162 expression on circulating
neutrophils in monkeys, but CD162 expression was
induced by IL-8 and GM-CSF was induced by IL-6 [61].
IL-6 blockade rapidly decreased the number of
circulating neutrophils in arthritic animals and RA
patients [62,63], suggesting that IL-6 plays a dominant
role in neutrophilia in arthritis and that IL-6 blockade
inhibits demargination of intravascular neutrophils into
circulating blood.
Immune responses
IL-6 was originally identified as a B-cell differentiation
factor. IL-6 enhances the production of IgM, IgG and IgA
in B-cells activated with Staphylococcus aureus Cowan I
or pokeweed mitogen. Conversely, anti-IL-6 antibodies
inhibit pokeweed mitogen-induced Ig production from
peripheral blood mononuclear cells without affecting cell
proliferation, indicating that IL-6 is required for antibody
production in B-cells [64]. IL-6 promotes antibody
production by promoting the B-cell helper capabilities
of CD4 + T-cells through increased IL-21 production,
suggesting that IL-6 could be a potential co-adjuvant to
enhance humoral immunity [65].
Autoantibody production is induced by the overproduction of IL-6. In patients with cardiac myxoma, a
benign intra-atrial heart tumour that produces a large
amount of IL-6, autoimmune symptoms are ameliorated
when the tumour cells are resected [66]. In transgenic
mice that overproduce IL-6, hypergammaglobulinaemia
and autoantibody production are observed [67]. These
facts suggest that IL-6 causes B-cell abnormalities
associated with the inflammatory process. Moreover, IL6 blockade suppresses autoantibody production in lupusprone NZB/NZW F1 mice, despite the fact that they
do not have elevated IL-6 levels [68]. This phenomenon
can be explained by the fact that B-cells in this strain
of mice show hypersensitivity to IL-6 [69]. A similar
phenomenon is reported in patients with systemic lupus
erythematosus [70].
B-cells play an essential role in the pathogenesis of
RA, because B-cell depletion therapy by an anti-CD20
antibody is effective in RA therapy [71]. IL-6 transsignalling has been shown to induce PBEF (pre-B-cell
colony-enhancing factor) in synovial fibroblast cells [72].
PBEF was discovered as a cytokine for the differentiation
of B-cells [73]. Therefore B-cell maturation induced by
IL-6 itself and IL-6-induced PBEF may play important
roles in the pathogenesis of RA.
IL-6 is involved in the proliferation and differentiation
of helper T-cells. IL-6 significantly enhances the
proliferation of T-cells when T-cells are stimulated with a
mitogen [74,75]. In addition, IL-6 blockade suppresses
anti-CD3 antibody-induced and anti-CD28 antibodyinduced CD4 + T-cell proliferation, and this suppression
is achieved by the inhibition of IL-2 production and the
induction of Tregs (regulatory T-cells) [76].
CD4 + helper T-cells have been classified as Th 1 and
Th 2 cells on the basis of their cytokine production profiles, and IL-6 promotes IL-4-induced Th 2 differentiation
and inhibits IL-12-induced Th 1 differentiation [77]. Th 17
cells, which produce IL-17 in autoimmune pathology,
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Figure 4 Differentiation of CD4 helper T-cells
have become recognized as a separate subset. In vitro
studies in mice have shown that the co-stimulation of
IL-6 and TGF-β is essential for the differentiation of
Th 17 cells from naı̈ve CD4 + T-cells [78]. Furthermore,
the involvement of IL-6 in induction of Th 17 cells has
been reported in several autoimmune disease models: an
anti-IL-6R antibody suppressed the onset of disease and
concomitantly inhibited the appearance of Th 17 cells [79–
83] (Figure 4).
Th 17 cells have also been identified in human blood
and inflamed tissues, but they seem to exhibit different
features from murine Th 17 cells [84]. First, human Th 17
cells express CCR6 and IL-23R, but also IL-12Rβ2 and
CD161. Secondly, human Th 17 cells express T-bet in
addition to ROR (retinoic acid-receptor-related orphan
receptor) γ t and can be induced to produce IFN-γ in
addition to IL-17A in the presence of IL-12. Finally,
although murine Th 17 cells originate from a precursor
common to Fox (forkhead box) p3 + Tregs by IL-6 and
TGF-β stimulation, human Th 17 cells originate from
CD161 + CD4 + precursors, which constitutively express
RORγ t and IL-23R, in response to the combined activity
of IL-1β and IL-23. TGF-β does not play a direct role
in human Th 17 differentiation. It is reported that IL6 enhances IL-1β-induced Th 17 polarization of human
naı̈ve CD4 + T-cells [85,86]. Further studies are necessary
to clarify the involvement of IL-6 in the development of
human Th 17 cells, especially in vivo.
Bone metabolism
The skeleton is a dynamic organ in which mineralized
bone is continuously resorbed by osteoclasts and new
bone is formed by osteoblasts. This process, known
as bone remodelling, is normally highly regulated to
maintain a normal amount of bone.
A study using IL-6-deficient mice showed that neither
gross structural abnormalities nor significant differences
in trabecular bone volume were observed in the bones
of the mutant mice [87]. Moreover, the IL-6-deficient
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mice had a normal number of osteoclasts and normally
active bone resorption, as measured by the extent of
eroded bone surface containing osteoclasts and the number of osteoclast precursors in the bone marrow [CFUGM (colony-forming unit-granulocyte, monocyte)] was
normal [87]. These lines of evidence suggest that IL-6
is not required for normal bone development and
is not essential for promoting osteoclastogenesis and
osteoclastic bone-resorbing activity.
Oestrogen deficiency is a cause of bone loss in patients
with postmenopausal osteoporosis. In ovariectomized
mice, an animal model of postmenopausal osteoporosis,
treatment with an anti-IL-6 antibody failed to prevent
bone loss or the increase in bone resorption and
osteoclastogenesis [88]. Although oestrogen is thought
to regulate the secretion of cytokines that are produced
in the bone microenvironment and influence bone
remodelling, there is a study showing that IL-6
expression was not induced in bone-related tissues after
ovariectomy [89]. In contrast, there is a report showing
that ovariectomy did not induce bone loss in IL-6deficient mice [87]. Therefore the involvement of IL-6
in postmenopausal osteoporosis is still controversial.
However, IL-6 is suggested to have a pathogenetic
role in the abnormal bone resorption in RA, MM
and other bone diseases characterized by excessive
osteoclastogenesis and focal osteolytic lesions. Synovial
fluids from RA patients contain high levels of IL-6
and sIL-6R, and the IL-6–sIL-6R complex stimulates
osteoclast formation in a co-culture system of mouse
bone marrow cells and osteoblastic cells [90]. This may
be due to the induction of RANKL on the surface of
stromal/osteoblastic cells by IL-6 + sIL-6R stimulation
[91].
We have also reported that IL-6 + sIL-6R stimulation
induces RANKL expression in RA-FLS. In a co-culture
of RA-FLS and osteoclast precursor cells (RAW 264.7
cells) in the presence of IL-6 + sIL-6R, the RAW 264.7
cells differentiated into mature osteoclasts, and this
phenomenon was blocked by an anti-RANKL antibody
[24] (Figure 5).
On the other hand, IL-6 acts directly on osteoclast
precursor cells and suppresses their differentiation by
regulating the transcription of specific genes related
to MAPK phosphatases and the ubiquitin pathway
[92]. However, we found that ICAM-1/LAF (leucocyte
function-associated antigen)-1 signalling may be involved
in the discrepancy between the effects of IL-6 on
osteoclast differentiation in a mono-culture system and
in a co-culture system. Briefly, addition of sICAM-1
(soluble ICAM-1) reverses the IL-6-induced suppression
of osteoclast formation in a mono-culture system [93].
Collectively, IL-6 induces abnormal osteoclastogenesis
in the inflamed joints of RA patients via the induction
of RANKL expression in osteoblastic cells and synovial
cells in the presence of ICAM-1. TCZ therapy in RA
IL-6 signalling and its biological activities
of TIMPs (tissue inhibitors of MMPs), which are
endogenous inhibitors of MMPs, in human chondrocytes
and synovial fibroblasts, suggesting that IL-6 plays a
role in extracellular matrix turnover [99]. Improvement
in cartilage turnover markers [PIIANP (N-terminal
propeptide of type IIA collagen) and HELIX-II (type
II collagen helical peptide)] has been reported in TCZtreated RA patients [94]. Moreover, TCZ decreases serum
MMP-3 levels [100]. These findings suggest that the
preventive effect of TCZ on cartilage degeneration is
mediated by suppression of the IL-6-induced production
of MMPs and ADAMTS.
Figure 5 Effect of IL-6 on bone metabolism in RA synovium
patients significantly prevents the progression of joint
destruction, as assessed by radiography, and improves
levels of the bone resorption marker CTX-1 (C-terminal
cross-linking telopeptide of type I collagen) [94].
Cartilage metabolism
Growth impairment is a common manifestation of
several childhood diseases with chronic inflammation
and/or severe recurrent infections, such as juvenile
rheumatoid arthritis, Crohn’s disease, cystic fibrosis
and immunodeficiencies, all of which are characterized
by elevated levels of IL-6 and decreased levels of
IGF-1 (insulin-like growth factor-1). IL-6 transgenic
mice (NSE/hIL-6 strain) represent a model of the
growth impairment associated with childhood chronic
inflammatory diseases. Complete correction of the
growth defects, as well as normalization of the IGF1 levels, is obtained by the neutralization of IL-6
[95]. Longitudinal bone growth occurs at the growth
plates by endochondral ossification, which involves the
two steps of chondrogenesis and ossification. These
are regulated by a multitude of genetic and hormonal
factors, growth factors, environment and nutrition. The
GH (growth hormone)/IGF-1 axis is considered to have
a particularly important regulatory effect on growth
plate chondrogenesis. Nakajima et al. [96] reported that
IL-6 directly inhibits insulin-induced differentiation of
chondrogenic progenitor cells. These results strongly
suggest that IL-6 inhibits chondrogenesis via reduction
in IGF-1 levels and via inhibiting differentiation of
chondrogenic progenitor cells.
Regarding joint cartilage, MMPs and ADAMTS
(ADAM with thrombospondin motifs) are thought to
play crucial roles in cartilage matrix degeneration. IL6 induces the production of MMPs (MMP-1, MMP-3
and MMP-13) and ADAMTS-4 from chondrocytes and
synovial cells [97,98]. Interestingly, IL-6 synergistically
increases MMP production with IL-1 via the induction
of IL-1R (IL-1 receptor) [98]. On the other hand, it
is reported that IL-6 + sIL-6R induces the production
Anaemia of chronic diseases
Anaemia is often observed in patients with chronic
inflammatory diseases, such as RA, inflammatory bowel
disease and cancer, and is called ACD (anaemia of chronic
disease). ACD is characterized by hypoferraemia in the
presence of adequate iron stores. Inflammatory cytokines
are thought to play important roles in ACD.
Anaemia induced in monkey collagen-induced arthritis is characterized by decreased serum iron and
transferrin saturation and by elevated serum ferritin, and
the severity of anaemia is correlated with serum IL6 levels [101]. Hepcidin is a master regulator of iron
homoeostasis in humans and other mammals [102]. It
inhibits the absorption of iron in the small intestine and
the release of recycled iron from macrophages, effectively
decreasing the delivery of iron to maturing erythrocytes
in the bone marrow [103]. In fact, mice genetically
engineered to overproduce hepcidin die of severe iron
deficiency shortly after birth [104].
IL-6 induces hepcidin production in liver cells [105].
Administration of TCZ to monkeys with collageninduced arthritis rapidly improved anaemia and induced
a rapid, but transient, reduction in serum hepcidin.
Hepcidin mRNA expression was more potently induced
by serum from arthritic monkeys than that from healthy
animals, and this was inhibited by the addition of TCZ.
These lines of evidence indicate that TCZ improves
anaemia in monkey arthritis via the inhibition of IL-6induced hepcidin production [106] (Figure 6).
Moreover, TCZ treatment resulted in a rapid
reduction in serum hepcidin-25 in patients with
Castleman’s disease. Long-term reductions, accompanied
by progressive normalization of iron-related parameters
and improvement in symptoms, were observed after the
start of TCZ treatment, indicating that IL-6 plays an
essential role in the induction of hepcidin in Castleman’s
disease [107].
Lipid metabolism
IL-6 transgenic mice had low total cholesterol and
TAG [triacylglycerol (triglyceride)] levels compared with
littermates, and treatment with an anti-IL-6R antibody
increased their lipid profiles to normal levels [108]. It has
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Figure 6 Effect of IL-6 on iron metabolism
been shown that high levels of TAG and VLDL (verylow-density lipoprotein) are present in IL-6-deficient
mice [109]. B-cells in the germinal centres of hyperplastic
lymph nodes in patients with Castleman’s disease
have abnormal production of IL-6 [110], and also have
hypolipidaemia [111]. Moreover, in patients with early
active RA and high-grade inflammation, cholesterol and
TAG levels appear normal or even low [112]. These lines
of evidence clearly suggest that IL-6 plays an important
role in lipid metabolism.
We have reported that IL-6 injection into mice
decreased total cholesterol and TAG levels [113]. In this
model, expression of the VLDL receptor, which plays a
role in the delivery of fatty acids derived from VLDLTAGs from the blood to peripheral tissues, was upregulated in IL-6-treated mice. These results suggested
that the induction of VLDL receptor by IL-6 may
be related to the hypolipidaemia. Several reports have
described the function of IL-6 in lipid metabolism in
adipose tissue. Interstitial IL-6 concentrations in adipose
tissue are approximately 100 times as high as in plasma,
implying an important autocrine and paracrine regulatory
function in this tissue [114]. IL-6 has lipolytic properties
and increases lipolysis of adipose tissue and adipocytes
in vitro [115,116]. Consistent with these in vitro studies,
IL-6 infusion in humans increased non-esterified (‘free’)
fatty acid and whole-body fat oxidation [117].
IL-6 treatment produced a significant induction of
PPAR (peroxisome-proliferator-activated receptor) α
and reduction of SREBP (sterol-regulatory-elementbinding protein)-1c mRNA in the hepatoma cell line
Hep3B-cells. PPARα regulates decomposition of fatty
acids through mitochondrial and peroxisomal oxidation
[118]. It has been shown that PPARα deficiency abolishes
the normal diurnal variations in the expression of
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lipogenic genes, such as those encoding FAS (fatty acid
synthase), ACC (acetyl-CoA carboxylase) and HMGCoA (3-hydroxy-3-methylglutaryl-CoA) reductase, in
the liver [119]. On the other hand, the SREBP family
is a group of transcription factors that activate genes
encoding enzymes regulating cholesterol and fatty acid
biosynthesis. In particular, SREBP-1c preferentially
enhances transcription of genes associated with fatty
acid synthesis, including FAS [120,121]. Furthermore,
we have observed a similar phenomenon in mice treated
with IL-6; i.e. in the liver from such mice, PPARα
expression was indeed increased and SREBP-1c was
decreased [122]. From these results, it can be seen that
IL-6 accelerates decomposition of lipids and inhibits the
synthesis of lipids, leading to a reduction in serum lipid
levels (Figure 7).
It has been reported that treatment of RA patients
with TCZ increased blood levels of total cholesterol,
TAG and HDL-cholesterol in a manner inversely related
to the disease activity of RA [123]. It is also reported
that blockade of TNF-α increased blood levels of total
cholesterol, TAG and HDL-cholesterol, and that the
persistent inflammatory condition reflected by elevated
serum TNF-α levels results in low levels of total
cholesterol and TAG in RA [124–126]. This strongly
suggests that the inhibition of IL-6 production induced
by TNF-α blockade results in an increase in lipids.
However, although these drugs increase total cholesterol
and TAG, neither TNF-α blockade nor TCZ changes the
atherogenic index (total cholesterol/HDL) [127,128].
Cancer
Chronic inflammation plays an important role in
human carcinogenesis. There are many reports describing
elevated serum levels of IL-6 in cancer patients, which
are related to disease severity and outcome [129–132].
IL-6 has been implicated in the modulation of growth
and differentiation in many cancers, and is associated
with poor prognosis in renal cell carcinoma, ovarian
cancer, lymphoma, melanoma and prostate cancer [133].
By activating ERK1/2, IL-6 stimulates tumour cell
proliferation [134–136]. IL-6 is an important regulator
of cell survival, providing tumour cells with a mechanism
to escape cell death induced by stress and cytotoxic drugs.
Additionally, the physiological role of IL-6 has been
shown to promote not only tumour proliferation, but
also metastasis and symptoms of cachexia [137–140].
MM is a malignancy of plasma cells and is the
most common malignant lymphoma in adults. It is
characterized by localization of tumour cells to the bone
marrow, where these cells disseminate and induce
bone diseases. The interaction between MM cells and
stromal cells in the bone marrow microenvironment
stimulates the production of cytokines, growth factors
and adhesion molecules, which together play an
important role in the proliferation and localization of
IL-6 signalling and its biological activities
Figure 7 Effect of IL-6 on lipid metabolism
VLDL-R, VLDL receptor.
MM cells in the bone marrow. MM cells cause osteolysis,
leading to bone pain and hypercalcaemia. Kawano et al.
[141] reported that IL-6 is a major growth factor for
MM cells. In approximately half of all MM patients,
proliferation of cultured MM cells is observed to be
mediated by an autocrine loop, and it is now well known
that IL-6 produced by the bone marrow environment is
the major cytokine involved in the growth and survival
of MM cells [142]. Moreover, IL-6 is well known to
be an essential factor in the survival of MM cells,
since it prevents apoptosis of MM cells induced by
different stimuli such as dexamethasone, Fas and serum
deprivation. The IL-6–sIL-6R complex is more potent
than IL-6 alone in up-regulating both Bcl-xL and Mcl-l
in native MM cells, which do not express IL-6R on the
cell surface [143].
The expression of IL-6 and IL-6R and the role of IL-6
as a growth factor in prostate cancer are well documented
[144]. IL-6 is responsible for resistance to apoptosis and
increased levels of an anti-apoptotic member of the Bcl-2
family in the advanced prostate cancer cell line LNCaP
[141]. Moreover, since the growth of prostate cancer
cells depends on the presence of androgens, almost all
patients with advanced prostate cancer respond initially
to androgen deprivation and anti-androgen therapy.
Because IL-6 stimulates androgen synthesis and ARs
(androgen receptors) in prostate cancer cells [145], it is
possible that IL-6 diminishes the therapeutic effect of
anti-androgen treatment in prostate cancer [145]. On the
other hand, in AR-negative prostate cancer cells, IL-6 is
known as an inhibitor of apoptosis [146].
Cancer-related anorexia and cachexia are serious
complications associated with malignant disease [147].
The features of cachexia are anaemia, abnormalities of
liver function, fatigue and vomiting. Elevated serum
IL-6 in patients with pancreatic cancer and correlation
with cachexia has been observed [148]. As described
above, IL-6 is related to iron metabolism. Moreover, IL6 also has a regulatory role related to excess glucose
metabolism and muscle loss [149]. Previously, we have
reported that IL-6 is essential for cancer cachexia in
a syngeneic mouse model, in which treatment with an
anti-IL-6 antibody prevented the induction of cancer
cachexia [150]. In addition, in syngeneic mice, injection
of IL-6 cDNA-transfected Lewis lung carcinoma cells
resulted in unaltered net tumour growth rate, but caused
weight loss and shortened survival [151]. It is reported
that an anti-human IL-6 antibody (ALD518) reversed
fatigue and reduced loss of lean body mass ( − 0.19 kg
in patients taking ALD518 compared with − 1.50 kg in
those taking placebo) in patients with advanced non-small
cell lung cancer [152], and that in these patients ALD518
increased haemoglobin, haematocrit, mean corpuscular
haemoglobin and albumin, and raised haemoglobin levels
to 12 g/dl in 58 % of patients with haemoglobin
levels of 11 g/dl at baseline. ALD518 may be a novel
non-erythropoietic-stimulating agent for cancer-related
anaemia [153].
Patients with long-standing ulcerative colitis carry a
much higher risk of developing colon cancer, suggesting
a role of the immune system as a tumour promoter in
the colon. However, the reasons for this increased cancer
occurrence are not fully understood. A study has shown
that IL-6, which is produced in innate immune cells
within the lamina propria in response to intestinal injury,
enhances proliferation of tumour-initiating cells and
protects normal and pre-malignant intestinal epithelial
cells from apoptosis during acute colonic inflammation
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and CAC (colitis-associated cancer) induction [154]. A
more recent study has also shown that, in azoxymethaneinduced colonic tumours in ulcerative colitis models,
the appearance of tumours was accompanied by the
co-appearance of an F4/80 + CD11bhigh Gr1low (M2)
macrophage subset, which is a source of tumourpromoting factors, including IL-6 [155]. These results
suggest that IL-6 blockade could be an approach for the
therapy of CAC.
Table 1 Possible disease targets for IL-6 blockade by TCZ
CLINICAL APPLICATION OF IL-6 BLOCKERS
Chronic inflammatory disease
As described above, IL-6 has vast variety of biological
activities and plays important roles in inflammation,
the immune response, haemopoiesis etc. Therefore IL-6
blockade is anticipated to constitute a novel treatment
strategy for inflammatory and autoimmune diseases,
as well as for cancers. TCZ, a humanized an anti(human IL-6R) monoclonal antibody, was the first IL6 blocker to be developed. TCZ blocks IL-6-mediated
signal transduction through the inhibition of IL-6
binding to mIL-6R and sIL-6R [156]. TCZ is approved
for the therapy of Castleman’s disease, RA, and JIA
(polyarticular JIA and sJIA).
Castleman’s disease
Castleman’s disease is a lymphoproliferative disease
with benign hyperplastic lymph nodes characterized
by follicular hyperplasia and capillary proliferation
accompanied by endothelial hyperplasia. IL-6 is
produced in high levels in the hyperplastic lymph nodes,
and IL-6 is the key element responsible for the various
clinical symptoms [107]. Two open-label clinical trials
have shown that TCZ administered at 8 mg/kg of body
weight every 2 weeks had a marked effect on clinical
symptoms and on laboratory findings, as well as on
histologically determined amelioration [108,157]. TCZ
was approved as an orphan drug for Castleman’s disease
in 2005 in Japan.
Rheumatoid arthritis
RA is a chronic progressive autoimmune inflammatory
disease with unknown aetiology that particularly affects
the joints of the hands and feet. The synovial tissue of
affected joints is infiltrated by inflammatory cells, such
as macrophages and lymphocytes, leading to hyperplasia
with neovascularization, which causes joint swelling,
stiffness and pain. This ultimately leads to cartilage
destruction and bone resorption in the joints, with some
patients suffering permanent disability. The biological
activities of IL-6 and the elevation of IL-6 in the serum
and the synovial fluids of RA patients indicate that IL-6
is one of the key cytokines involved in the development
of RA [158,159]. Seven Phase III clinical trials of TCZ
carried out in Japan and worldwide have revealed its
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TCZ is an anti-IL-6 antibody produced by Chugai/Roche.
Disease
Candidate disease target
Systemic autoimmune disease
Systemic lupus erythematosus
Systemic sclerosis
Giant cell arteritis and Takayasu arteritis
Polymyositis
Crohn’s disease
Relapsing polychondritis
Acquired haemophilia A
Adult-onset Still’s disease
Reactive AA amyloidosis
Polymyalgia rheumatica
Remitting seronegative symmetrical
synovitis with pitting oedema
Spondyloarthritides
Behcet’s disease
GVHD (graft-versus-host disease)
MM
Organ-specific autoimmune disease
Cancer
efficacy, both as a monotherapy or combined with
DMARDs (disease-modifying anti-rheumatic drugs), for
adult patients with moderate-to-severe RA [94,160–
165]. Moreover, SAMURAI (Study of Active Controlled
Monotherapy Used for Rheumatoid Arthritis, an IL6 Inhibitor) [94] and LITHE (TociLIzumab safety
and THE prevention of structural joint damage trial)
[164] proved that radiological damage of joints was
significantly inhibited by TCZ treatment. As a result,
TCZ has now been approved for the treatment of RA in
many countries.
Systemic juvenile idiopathic arthritis
sJIA is a subtype of chronic childhood arthritis that
leads to joint destruction and functional disability,
accompanied by systemic inflammation. This longlasting inflammation also causes spike fever, anaemia and
impairment of growth. Moreover, the acute complication
known as macrophage activation syndrome is associated
with serious morbidity. IL-6 has been reported to be
markedly elevated in blood and synovial fluid, and the IL6 level has been shown to correlate with disease activity
[166,167]. TCZ showed outstanding efficacy in a randomized double-blind placebo-controlled withdrawal
Phase III trial for 56 patients with sJIA, who had been
refractory to conventional treatment regimens [168]. It
was approved in 2008 in Japan as the first biological drug
for sJIA. This efficacy was maintained in a recent global
Phase III trial (TENDER); 112 patients with severe sJIA
refractory to conventional treatments, including TNF
and IL-1 inhibitors, were enrolled [169].
As shown in Table 1, the treatment of many
inflammatory diseases by TCZ shows beneficial effects
IL-6 signalling and its biological activities
Table 2 Novel IL-6 inhibitors in clinical trials
Name of inhibitor (type of inhibitor; company)
Disease
Candidate disease target
CNTO-328 (chimaeric anti-IL-6 antibody; Centocor)
Cancer
CNTO-136 (humanized anti-IL-6 antibody/Centocor)
Systemic autoimmune disease
REGN-88 (anti-IL-6R antibody; Regeneron/Sanofi-Aventis)
Systemic autoimmune disease
ALD518/BMS-945429 (anti-IL-6 antibody; Alder/BMS)
Systemic autoimmune disease
CDP6038 (anti-IL-6 antibody; UCB)
C326 (avimer protein; Avidia)
FE301 (sgp130-Fc fusion protein; Ferring/Conaris Research Institute)
Cancer
Systemic autoimmune disease
Systemic autoimmune disease
Systemic autoimmune disease
MM
Prostate tumour
Renal cell carcinoma
Non-Hodgkin’s lymphoma
Cachexia
RA
Cutaneous lupus erythematosus
Systemic lupus erythematosus
RA
Spondyloarthritides
RA
Spondyloarthritides
Cachexia
RA
Crohn’s disease
Crohn’s disease
in pilot studies and clinical practices [170]. Future clinical
trials to evaluate the efficacy and safety of TCZ for
these diseases are essential for the identification of
new indications for TCZ. Basic research to clarify the
mechanism(s) of how IL-6 blockade exerts its efficacy is
also important.
In response to clinical success of TCZ, many other
IL-6 blockers are being developed for these diseases
(Table 2) [171,172]. However, to date, there is less
information about the differences between TCZ and
other IL-6 blockers. Further studies to address this issue
are necessary.
CONCLUSIONS
IL-6 participates in a broad spectrum of biological events,
such as immune responses, haemopoiesis and acute-phase
reactions. In contrast, overproduction of IL-6 production
has been implicated in the pathogenesis of a variety of
diseases, including several chronic inflammatory diseases
and cancer. Future studies to clarify the molecular
mechanisms of IL-6 functions and the use of inhibitors
of IL-6 signalling should provide information critical
to a better understanding of the molecular mechanisms
of diseases and the development of new therapeutic
methods.
REFERENCES
1 Hirano, T., Yasukawa, K., Harada, H., Taga, T, Watanabe,
Y., Matsuda, T., Kashiwamura, S., Nakajima, K., Koyama,
A., Iwamatsu, A. et al. (1986) Complementary DNA for a
novel human interleukin (BSF-2) that induces B
lymphocytes to produce immunoglobulin. Nature 324,
73–76
2 Sehgal, P. B., May, L. T., Tamm, I. and Vilcek, J. (1987)
Human β2 interferon and B-cell differentiation factor
BSF-2 are identical. Science 235, 731–732
3 Haegeman, G., Content, J., Volckaert, G., Derynck, R.,
Tavernier, J. and Fiers, W. (1986) Structural analysis of the
sequence coding for an inducible 26-kDa protein in
human fibroblasts. Eur. J. Biochem. 159, 625–632
4 Gauldie, J., Richards, C., Harnish, D., Lansdorp, P. and
Baumann, H. (1987) Interferon β2/B-cell stimulatory
factor type 2 shares identity with monocyte-derived
hepatocyte-stimulating factor and regulates the major
acute phase protein response in liver cells. Proc. Natl.
Acad. Sci. U.S.A. 84, 7251–7255
5 Mihara, M., Nishimoto, N. and Ohsugi, Y. (2005) The
therapy of autoimmune diseases by anti-interleukin-6
receptor antibody. Expert Opin. Biol. Ther. 5, 683–690
6 Hibi, M., Murakami, M., Saito, M., Hirano, T., Taga, T.
and Kishimoto, T. (1990) Molecular cloning and
expression of an IL-6 signal transducer, gp130. Cell 63,
1149–1157
7 Martens, A. S., Bode, J. G., Heinrich, P. C. and Graeve, L.
(2000) The cytoplasmic domain of the interleukin-6
receptor gp80 mediates its basolateral sorting in polarized
Madin–Darby canine kidney cells. J. Cell Sci. 113,
3593–3602
8 Rose-John, S. and Neurath, M. F. (2004) IL-6
trans-signaling: the heat is on. Immunity 20, 2–4
9 Narazaki, M., Yasukawa, K., Saito, T., Ohsugi, Y., Fukui,
H., Koishihara, Y., Yancopoulos, G. D., Taga, T. and
Kishimoto, T. (1993) 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 82, 1120–1126
10 Jostock, T., Müllberg, J., Ozbek, S., Atreya, R., Blinn, G.,
Voltz, N., Fischer, M., Neurath, M. F. and Rose-John, S.
(2001) Soluble gp130 is the natural inhibitor of soluble
interleukin-6 receptor transsignaling responses. Eur. J.
Biochem. 268, 160–167
11 Taga, T., Kawanishi, Y., Hardy, R. R., Hirano, T. and
Kishimoto, T. (1987) Receptors for B cell stimulatory
factor 2. Quantitation, specificity, distribution, and
regulation of their expression. J. Exp. Med. 166, 967–981
12 Stoyan, T., Michaelis, U., Schooltink, H., Van Dam, M.,
Rudolph, R., Heinrich, P. C. and Rose-John, S. (1993)
Recombinant soluble human interleukin-6 receptor.
Expression in Escherichia coli, renaturation and
purification. Eur. J. Biochem. 216, 239–245
C
The Authors Journal compilation
C
2012 Biochemical Society
153
154
M. Mihara and others
13 Rose-John, S., Hipp, E., Lenz, D., Legres, L. G., Korr, H.,
Hirano, T., Kishimoto, T. and Heinrich, P. C. (1991)
Structural and functional studies on the human
interleukin-6 receptor. Binding, cross-linking,
internalization, and degradation of interleukin-6 by
fibroblasts transfected with human interleukin-6-receptor
cDNA. J. Biol. Chem. 266, 3841–3846
14 Hashizume, M. and Mihara, M. (2009) Influence of
humanized anti-IL-6R antibody, tocilizumab on the
activity of soluble gp130, natural inhibitor of IL-6
signaling. Rheumatol. Int. 29, 397–401
15 Taga, T. and Kishimoto, T. (1997) Gp130 and the
interleukin-6 family of cytokines. Annu. Rev. Immunol.
15, 797–819
16 Dillon, S. R., Sprecher, C., Hammond, A., Bilsborough, J.,
Rosenfeld-Franklin, M., Presnell, S. R., Haugen, H. S.,
Maurer, M., Harder, B., Johnston, J. et al. (2004)
Interleukin 31, a cytokine produced by activated T cells,
induces dermatitis in mice. Nat. Immunol. 5, 752–760
17 Pflanz, S., Hibbert, L., Mattson, J., Rosales, R., Vaisberg,
E., Bazan, J. F., Phillips, J. H., McClanahan, T. K., de Waal
Malefyt, R. and Kastelein, R. A. (2004) WSX-1 and
glycoprotein 130 constitute a signal-transducing receptor
for IL-27. J. Immunol. 172, 2225–2231
18 Rochman, Y., Spolski, R. and Leonard, W. J. (2009) New
insights into the regulation of T cells by γ c family
cytokines. Nat. Rev. Immunol. 9, 480–490
19 Boulanger, M. J., Chow, D. C., Brevnova, E. E. and
Garcia, K. C. (2003) Hexameric structure and assembly of
the interleukin-6/IL-6α receptor/gp130 complex. Science
300, 2101–2104
20 Grötzinger, J., Kernebeck, T., Kallen, K. J. and Rose-John,
S. (1999) IL-6 type cytokine receptor complexes: hexamer
or tetramer or both? Biol. Chem. 380, 803–813
21 Hirano, T., Nakajima, K. and Hibi, M. (1997) Signaling
mechanisms through gp130: a model of the cytokine
system. Cytokine Growth Factor Rev. 8, 241–252
22 Starr, R. and Hilton, D. J. (1998) SOCS: suppressors of
cytokine signalling. Int. J. Biochem. Cell Biol. 30,
1081–1085
23 Hashizume, M. and Mihara, M. (2010) High molecular
weight hyaluronic acid inhibits IL-6-induced MMP
production from human chondrocytes by up-regulating
the ERK inhibitor, MKP-1. Biochem. Biophys. Res.
Commun. 403, 184–189
24 Hashizume, M., Hayakawa, N. and Mihara, M. (2008)
IL-6 trans-signalling directly induces RANKL on
fibroblast-like synovial cells and is involved in RANKL
induction by TNF-α and IL-17. Rheumatology 47,
1635–1640
25 LeMay, L. G., Vander, A. J. and Kluger, M. J. (1990) Role
of interleukin 6 in fever in rats. Am. J. Physiol. 258,
R798–R803
26 van Gameren, M. M., Willemse, P. H., Mulder, N. H.,
Limburg, P. C., Groen, H. J., Vellenga, E. and de Vries, E.
G. (1994) Effects of recombinant human interleukin-6 in
cancer patients: a phase I-II study. Blood 84, 1434–1441
27 Chen, Q., Wang, W. C., Bruce, R., Li, H., Schleider, D.
M., Mulbury, M. J., Bain, M. D., Wallace, P. K., Baumann,
H. and Evans, S. S. (2004) Central role of IL-6 receptor
signal-transducing chain gp130 in activation of L-selectin
adhesion by fever-range thermal stress. Immunity 20,
59–70
28 Chen, Q., Fisher, D. T., Clancy, K. A., Gauguet, J. M.,
Wang, W. C., Unger, E., Rose-John, S., von Andrian, U.
H., Baumann, H. and Evans, S. S. (2006) Fever-range
thermal stress promotes lymphocyte trafficking across
high endothelial venules via an interleukin 6
trans-signaling mechanism. Nat. Immunol. 7, 1299–1308
29 Banks, R. E., Forbes, M. A., Storr, M., Higginson, J.,
Thompson, D., Raynes, J., Illingworth, J. M., Perren, T. J.,
Selby, P. J. and Whicher, J. T. (1995) The acute phase
protein response in patients receiving subcutaneous IL-6.
Clin. Exp. Immunol. 102, 217–223
30 Nishimoto, N., Yoshizaki, K., Miyasaka, N., Yamamoto,
K., Kawai, S., Takeuchi, T., Hashimoto, J., Azuma, J. and
Kishimoto, T. (2004) Treatment of rheumatoid arthritis
with humanized anti-interleukin-6 receptor antibody: a
multicenter, double-blind, placebo-controlled trial.
Arthritis Rheum. 50, 1761–1769
C
The Authors Journal compilation
C
2012 Biochemical Society
31 Ito, H., Takazoe, M., Fukuda, Y., Hibi, T., Kusugami, K.,
Andoh, A., Matsumoto, T., Yamamura, T., Azuma, J.,
Nishimoto, N. et al. (2004) A pilot randomized trial of a
human anti-interleukin-6 receptor monoclonal antibody
in active Crohn’s disease. Gastroenterology 126, 989–996
32 Uchiyama, Y., Yorozu, K., Hashizume, M., Moriya, Y.
and Mihara, M. (2008) Tocilizumab, a humanized
anti-interleukin-6 receptor antibody, ameliorates joint
swelling in established monkey collagen-induced arthritis.
Biol. Pharm. Bull. 31, 1159–1163
33 Kopf, M., Baumann, H., Freer, G., Freudenberg, M.,
Lamers, M., Kishimoto, T., Zinkernagel, R., Bluethmann,
H. and Kohler, G. (1994) Impaired immune and
acute-phase responses in interleukin-6-deficient mice.
Nature 368, 339–342
34 Husby, G. (1992) Amyloidosis. Semin. Arthritis Rheum.
22, 67–82
35 Enriquez, R., Sirvent, A. E., Cabezuelo, J. B., Ull Laita,
M., Reyes, D. M. and Reyes, A. (1999) Crohn’s disease
with amyloid A amyloidosis and nephrotic syndrome.
Nephron 81, 123–124
36 Husby, G., Marhaug, G., Dowton, B., Sletten, K. and
Sipe, J. D. (1994) Serum amyloid A (SAA): biochemistry,
genetics and the pathogenesis of AA amyloidosis.
Amyloid 1, 119–137
37 Mihara, M., Shiina, M., Nishimoto, N., Yoshizaki, K.,
Kishimoto, T. and Akamatsu, K. (2004) Anti-interleukin 6
receptor antibody inhibits murine AA-amyloidosis. J.
Rheumatol. 31, 1132–1138
38 Okuda, Y. and Takasugi, K. (2006) Successful use of a
humanized anti-interleukin-6 receptor antibody,
tocilizumab, to treat amyloid A amyloidosis complicating
juvenile idiopathic arthritis. Arthritis Rheum. 54,
2997–3000
39 Nishida, S., Hagihara, K., Shima, Y., Kawai, M.,
Kuwahara, Y., Arimitsu, J., Hirano, T., Narazaki, M.,
Ogata, A., Yoshizaki, K. et al. (2009) Rapid improvement
of AA amyloidosis with humanised anti-interleukin 6
receptor antibody treatment. Ann. Rheum. Dis. 68,
1235–1236
40 Cressman, D. E., Greenbaum, L. E., DeAngelis, R. A.,
Ciliberto, G., Furth, E. E., Poli, V. and Taub, R. (1996)
Liver failure and defective hepatocyte regeneration in
interleukin-6-deficient mice. Science 274, 1379–1383
41 Sone, H., Sakauchi, M., Takahashi, A., Suzuki, H., Inoue,
N., Iida, K., Shimano, H., Toyoshima, H., Kawakami, Y.,
Okuda, Y. et al. (2001) Elevated levels of vascular
endothelial growth factor in the sera of patients with
rheumatoid arthritis correlation with disease activity. Life
Sci. 69, 1861–1869
42 Nakahara, H., Song, J., Sugimoto, M., Hagihara, K.,
Kishimoto, T., Yoshizaki, K. and Nishimoto, N. (2003)
Anti-interleukin-6 receptor antibody therapy reduces
vascular endothelial growth factor production in
rheumatoid arthritis. Arthritis Rheum. 48,
1521–1529
43 Hashizume, M., Hayakawa, N., Suzuki, M. and Mihara,
M. (2009) IL-6/sIL-6R trans-signalling, but not TNF-α
induced angiogenesis in a HUVEC and synovial cell
co-culture system. Rheumatol. Int. 29, 1449–1454
44 Kamishima, T., Tanimura, K., Shimizu, M., Matsuhashi,
M., Fukae, J., Kon, Y., Hagiwara, H., Narita, A., Aoki, Y.,
Kosaka, N. et al. (2011) Monitoring anti-interleukin 6
receptor antibody treatment for rheumatoid arthritis by
quantitative magnetic resonance imaging of the hand and
power Doppler ultrasonography of the finger. Skeletal
Radiol. 40, 745–755
45 Krzystolik, M. G., Afshari, M. A., Adamis, A. P.,
Gaudreault, J., Gragoudas, E. S., Michaud, N. A., Li, W.,
Connolly, E., O’Neill, C. A. and Miller, J. W. (2002)
Prevention of experimental choroidal neovascularization
with intravitreal anti-vascular endothelial growth factor
antibody fragment. Arch. Ophthalmol. 120, 338–346
46 Rosenfeld, P. J., Brown, D. M., Heier, J. S., Boyer, D. S.,
Kaiser, P. K., Chung, C. Y. and Kim, R. Y. (2006)
Ranibizumab for neovascular age-related macular
degeneration. N. Engl. J. Med. 355, 1419–1431
IL-6 signalling and its biological activities
47 Seddon, J. M., George, S., Rosner, B. and Rifai, N. (2005)
Progression of age-related macular degeneration:
prospective assessment of C-reactive protein, interleukin
6, and other cardiovascular biomarkers. Arch.
Ophthalmol. 123, 774–782
48 Izumi-Nagai, K., Nagai, N., Ozawa, Y., Mihara, M.,
Ohsugi, Y., Kurihara, T., Koto, T., Satofuka, S., Inoue, M.,
Tsubota, K. et al. (2007) Interleukin-6 receptor-mediated
activation of signal transducer and activator of
transcription-3 (STAT3) promotes choroidal
neovascularization. Am. J. Pathol. 170, 2149–2158
49 Ulich, T. R., del Castillo, J. and Guo, K. Z. (1989) In vivo
hematologic effects of recombinant interleukin-6 on
hematopoiesis and circulating numbers of RBCs and
WBCs. Blood 73, 108–110
50 Woodfin, A., Voisin, M. B. and Nourshargh, S. (2010)
Recent developments and complexities in neutrophil
transmigration. Curr. Opin. Hematol. 17, 9–17
51 Romano, M., Sironi, M., Toniatti, C., Polentarutti, N.,
Fruscella, P., Ghezzi, P., Faggioni, R., Luini, W., van
Hinsbergh, V., Sozzani, S. et al. (1997) Role of IL-6 and its
soluble receptor in induction of chemokines and
leukocyte recruitment. Immunity 6, 315–325
52 Modur, V., Li, Y., Zimmerman, G. A., Prescott, S. M. and
McIntyre, T. M. (1997) Retrograde inflammatory
signaling from neutrophils to endothelial cells by soluble
interleukin-6 receptor α. J. Clin. Invest. 100, 2752–2756
53 Suzuki, M., Hashizume, M., Yoshida, H. and Mihara, M.
(2010) Anti-inflammatory mechanism of tocilizumab, a
humanized anti-IL-6R antibody: effect on the expression
of chemokine and adhesion molecule. Rheumatol. Int. 30,
309–315
54 Kawashiri, S. Y., Kawakami, A., Iwamoto, N., Fujikawa,
K., Aramaki, T., Tamai, M., Arima, K., Kamachi, M.,
Yamasaki, S., Nakamura, H. et al. (2009) Proinflammatory
cytokines synergistically enhance the production of
chemokine ligand 20 (CCL20) from rheumatoid
fibroblast-like synovial cells in vitro and serum CCL20 is
reduced in vivo by biologic disease-modifying
antirheumatic drugs. J. Rheumatol. 36, 2397–2402
55 Rabe, B., Chalaris, A., May, U., Waetzig, G. H., Seegert,
D., Williams, A. S., Jones, S. A., Rose-John, S. and
Scheller, J. (2008) Transgenic blockade of interleukin 6
transsignaling abrogates inflammation. Blood 111,
1021–1028
56 Wipke, B. T. and Allen, P. M. (2001) Essential role of
neutrophils in the initiation and progression of a murine
model of rheumatoid arthritis. J. Immunol. 167,
1601–1608
57 Nandakumar, K. S., Svensson, L. and Holmdahl, R. (2003)
Collagen type II-specific monoclonal antibody-induced
arthritis in mice: description of the disease and the
influence of age, sex, and genes. Am. J. Pathol. 163,
1827–1837
58 Eyles, J. L., Hickey, M. J., Norman, M. U., Croker, B. A.,
Roberts, A. W., Drake, S. F., James, W. G., Metcalf, D.,
Campbell, I. K. and Wicks, I. P. (2009) A key role for
G-CSF-induced neutrophil production and trafficking
during inflammatory arthritis. Blood 112, 5193–5201
59 Jung, U. and Ley, K. (1997) Regulation of E-selectin,
P-selectin, and intercellular adhesion molecule 1
expression in mouse cremaster muscle vasculature.
Microcirculation 4, 311–319
60 Suwa, T., Hogg, J. C., Quinlan, K. B. and Van Eeden, S. F.
(2002) The effect of interleukin-6 on L-selectin levels on
polymorphonuclear leukocytes. Am. J. Physiol. Heart
Circ. Physiol. 283, H879–H884
61 Hashizume, M., Higuchi, Y., Uchiyama, Y. and Mihara,
M. (2011) IL-6 plays an essential role in neutrophilia
under inflammation. Cytokine 54, 92–99
62 Nishimoto, N., Yoshizaki, K., Maeda, K., Kuritani, T.,
Deguchi, H., Sato, B., Imai, N., Suemura, M., Kakehi, T.,
Takagi, N. and Kishimoto, T. (2003) Toxicity,
pharmacokinetics, and dose-finding study of repetitive
treatment with the humanized anti-interleukin 6 receptor
antibody MRA in rheumatoid arthritis. Phase I/II clinical
study. J. Rheumatol. 30, 1426–1435
63 Maini, R. N., Taylor, P. C., Szechinski, J., Pavelka, K.,
Bröll, J., Balint, G., Emery, P., Raemen, F., Petersen, J.,
Smolen, J., Thomson, D. and Kishimoto, T. (2006)
Double-blind randomized controlled clinical trial of the
interleukin-6 receptor antagonist, tocilizumab, in
European patients with rheumatoid arthritis who had an
incomplete response to methotrexate. Arthritis Rheum.
54, 2817–2829
64 Muraguchi, A., Hirano, T., Tang, B., Matsuda, T., Horii,
Y., Nakajima, K. and Kishimoto, T. (1988) The essential
role of B cell stimulatory factor 2 (BSF-2/IL-6) for the
terminal differentiation of B cells. J. Exp. Med. 167,
332–344
65 Dienz, O., Eaton, S. M., Bond, J. P., Neveu, W., Moquin,
D., Noubade, R., Briso, E. M., Charland, C., Leonard, W.
J., Ciliberto, G. et al. (2009) The induction of antibody
production by IL-6 is indirectly mediated by IL-21
produced by CD4 + T cells. J. Exp. Med. 206, 69–78
66 Hirano, T., Taga, T., Yasukawa, K., Nakajima, K.,
Nakano, N., Takatsuki, F., Shimizu, M., Murashima, A.,
Tsunasawa, S., Sakiyama, F. and Kishimoto, T. (1987)
Human B-cell differentiation factor defined by an
anti-peptide antibody and its possible role in
autoantibody production. Proc. Natl. Acad. Sci. U.S.A.
84, 228–231
67 Suematsu, S., Matsuda, T., Aozasa, K., Akira, S., Nakano,
N., Ohno, S., Miyazaki, J., Yamamura, K., Hirano, T. and
Kishimoto, T. (1989) IgG1 plasmacytosis in interleukin 6
transgenic mice. Proc. Natl. Acad. Sci. U.S.A. 86,
7547–7551
68 Mihara, M., Takagi, N., Takeda, Y. and Ohsugi, Y. (1998)
IL-6 receptor blockage inhibits the onset of autoimmune
kidney disease in NZB/W F1 mice. Clin. Exp. Immunol.
112, 397–402
69 Mihara, M., Fukui, H., Koishihara, Y., Saito, M. and
Ohsugi, Y. (1990) Immunologic abnormality in NZB/W
F1 mice. Thymus-independent expansion of B cells
responding to interleukin-6. Clin. Exp. Immunol. 82,
533–537
70 Kitani, A., Hara, M., Hirose, T., Harigai, M., Suzuki, K.,
Kawakami, M., Kawaguchi, Y., Hidaka, T., Kawagoe, M.
and Nakamura, H. (1992) Autostimulatory effects of IL-6
on excessive B cell differentiation in patients with
systemic lupus erythematosus: analysis of IL-6
production and IL-6R expression. Clin. Exp. Immunol.
88, 75–83
71 Dörner, T., Radbruch, A. and Burmester, G. R. (2009)
B-cell-directed therapies for autoimmune disease. Nat.
Rev. Rheumatol. 5, 433–441
72 Nowell, M. A., Richards, P. J., Fielding, C. A.,
Ognjanovic, S., Topley, N., Williams, A. S., BryantGreenwood, G. and Jones, S. A. (2006) Regulation of
pre-B cell colony-enhancing factor by STAT-3-dependent
interleukin-6 trans-signaling: implications in the
pathogenesis of rheumatoid arthritis. Arthritis Rheum.
54, 2084–2095
73 Samal, B., Sun, Y., Stearns, G., Xie, C., Suggs, S. and
McNiece, I. (1994) Cloning and characterization of the
cDNA encoding a novel human pre-B-cell
colony-enhancing factor Mol. Cell. Biol. 14, 1431–1437
74 Lotz, M., Jirik, F., Kabouridis, P., Tsoukas, C., Hirano, T.,
Kishimoto, T. and Carson, D. A. (1988) B cell stimulating
factor 2/interleukin 6 is a costimulant for human
thymocytes and T lymphocytes. J. Exp. Med. 167,
1253–1258
75 Okazaki, M., Yamada, Y., Nishimoto, N., Yoshizaki, K.
and Mihara, M. (2002) Characterization of anti-mouse
interleukin-6 receptor antibody. Immunol. Lett. 84,
231–240
76 Yoshida, H., Hashizume, M., Suzuki, M. and Mihara, M.
(2010) Anti-IL-6 receptor antibody suppressed T cell
activation by inhibiting IL-2 production and inducing
regulatory T cells. Eur. J. Pharmacol. 634, 178–183
77 Diehl, S. and Rincón, M. (2002) The two faces of IL-6 on
Th1/Th2 differentiation. Mol. Immunol. 39, 531–536
78 Bettelli, E., Carrier, Y., Gao, W., Korn, T., Strom, T. B.,
Oukka, M., Weiner, H. L. and Kuchroo, V. K. (2006)
Reciprocal developmental pathways for the generation of
pathogenic effector TH 17 and regulatory T cells. Nature
441, 235–238
C
The Authors Journal compilation
C
2012 Biochemical Society
155
156
M. Mihara and others
79 Iwanami, K., Matsumoto, I., Tanaka-Watanabe, Y., Inoue,
A., Mihara, M., Ohsugi, Y., Mamura, M., Goto, D., Ito, S.,
Tsutsumi, A. et al. (2008) Crucial role of the
interleukin-6/interleukin-17 cytokine axis in the
induction of arthritis by glucose-6-phosphate isomerase.
Arthritis Rheum. 58, 754–763
80 Fujimoto, M., Serada, S., Mihara, M., Uchiyama, Y.,
Yoshida, H., Koike, N., Ohsugi, Y., Nishikawa, T.,
Ripley, B., Kimura, A. et al. (2008) Interleukin-6 blockade
suppresses autoimmune arthritis in mice by the inhibition
of inflammatory Th17 responses. Arthritis Rheum. 58,
3710–3719
81 Serada, S., Fujimoto, M., Mihara, M., Koike, N., Ohsugi,
Y., Nomura, S., Yoshida, H., Nishikawa, T., Terabe, F.,
Ohkawara, T. et al. (2008) IL-6 blockade inhibits the
induction of myelin antigen-specific Th17 cells and Th1
cells in experimental autoimmune encephalomyelitis.
Proc. Natl. Acad. Sci. U.S.A. 105, 9041–9046
82 Yoshimura, T., Sonoda, K. H., Ohguro, N., Ohsugi, Y.,
Ishibashi, T., Cua, D. J., Kobayashi, T., Yoshida, H. and
Yoshimura, A. (2009) Involvement of Th17 cells and the
effect of anti-IL-6 therapy in autoimmune uveitis.
Rheumatology 48, 347–354
83 Terabe, F., Fujimoto, M., Serada, S., Shinzaki, S., Iijima,
H., Tsujii, M., Hayashi, N., Nomura, S., Kawahata, H.,
Jang, M. H. et al. (2011) Comparative analysis of the
effects of anti-IL-6 receptor mAb and anti-TNF mAb
treatment on CD4 + T-cell responses in murine colitis.
Inflamm. Bowel Dis. 17, 491–502
84 Romagnani, S., Maggi, E., Liotta, F., Cosmi, L. and
Annunziato, F. (2009) Properties and origin of human
Th17 cells. Mol. Immunol. 47, 3–7
85 Acosta-Rodriguez, E. V., Napolitani, G., Lanzavecchia,
A. and Sallusto, F. (2007) Interleukins 1β and 6 but not
transforming growth factor-β are essential for the
differentiation of interleukin 17-producing human T
helper cells. Nat. Immunol. 8, 942–949
86 Liu, H. and Rohowsky-Kochan, C. (2008) Regulation of
IL-17 in human CCR6 + effector memory T cells. J.
Immunol. 180, 7948–7957
87 Poli, V., Balena, R., Fattori, E., Markatos, A., Yamamoto,
M., Tanaka, H., Ciliberto, G., Rodan, G. A. and
Costantini, F. (1994) Interleukin-6 deficient mice are
protected from bone loss caused by estrogen depletion.
EMBO J. 13, 1189–1196
88 Kimble, R. B., Bain, S. and Pacifici, R. (1997) The
functional block of TNF but not of IL-6 prevents bone
loss in ovariectomized mice. J. Bone Miner. Res. 12,
935–941
89 Vargas, S. J., Naprta, A., Lee, S. K., Kalinowski, J.,
Kawaguchi, H., Pilbeam, C. C., Raisz, L. G. and Lorenzo,
J. A. (1996) Lack of evidence for an increase in
interleukin-6 expression in adult murine bone, bone
marrow, and marrow stromal cell cultures after
ovariectomy. J. Bone Miner. Res. 11, 1926–1934
90 Kotake, S., Sato, K., Kim, K. J., Takahashi, N., Udagawa,
N., Nakamura, I., Yamaguchi, A., Kishimoto, T., Suda, T.
and Kashiwazaki, S. (1996) Interleukin-6 and soluble
interleukin-6 receptors in the synovial fluids from
rheumatoid arthritis patients are responsible for
osteoclast-like cell formation. J. Bone Miner. Res. 11,
88–95
91 O’Brien, C. A., Gubrij, I., Lin, S. C., Saylors, R. L. and
Manolagas, S. C. (1999) STAT3 activation in
stromal/osteoblastic cells is required for induction of the
receptor activator of NF-κB ligand and stimulation of
osteoclastogenesis by gp130-utilizing cytokines or
interleukin-1 but not 1,25-dihydroxyvitamin D3 or
parathyroid hormone. J. Biol. Chem. 274, 19301–19308
92 Yoshitake, F., Itoh, S., Narita, H., Ishihara, K. and Ebisu,
S. (2008) Interleukin-6 directly inhibits osteoclast
differentiation by suppressing receptor activator of
NF-κB signaling pathways. J. Biol. Chem. 283,
11535–11540
93 Suzuki, M., Hashizume, M., Yoshida, H., Shiina, M. and
Mihara, M. (2011) Intercellular adhesion molecule-1 on
synovial cells attenuated interleukin-6-induced inhibition
of osteoclastogenesis induced by receptor activator for
nuclear factor κB ligand. Clin. Exp. Immunol. 163, 88–95
C
The Authors Journal compilation
C
2012 Biochemical Society
94 Nishimoto, N., Hashimoto, J., Miyasaka, N., Yamamoto,
K., Kawai, S., Takeuchi, T., Murata, N., van der Heijde, D.
and Kishimoto, T. (2007) Study of active controlled
monotherapy used for rheumatoid arthritis, an IL-6
inhibitor (SAMURAI): evidence of clinical and
radiographic benefit from an x ray reader-blinded
randomised controlled trial of tocilizumab. Ann. Rheum.
Dis. 66, 1162–1167
95 De Benedetti, F., Alonzi, T., Moretta, A., Lazzaro, D.,
Costa, P., Poli, V., Martini, A., Ciliberto, G. and Fattori,
E. (1997) Interleukin 6 causes growth impairment in
transgenic mice through a decrease in insulin-like growth
factor-I. A model for stunted growth in children with
chronic inflammation. J. Clin. Invest. 99, 643–650
96 Nakajima, S., Naruto, T., Miyamae, T., Imagawa, T., Mori,
M., Nishimaki, S. and Yokota, S. (2009) Interleukin-6
inhibits early differentiation of ATDC5 chondrogenic
progenitor cells. Cytokine 47, 91–97
97 Hashizume, M. and Mihara, M. (2009) Desirable effect of
combination therapy with high molecular weight
hyaluronate and NSAIDs on MMP production.
Osteoarthritis Cartilage 17, 1513–1518
98 Suzuki, M., Hashizume, M., Yoshida, H., Shiina, M. and
Mihara, M. (2010) IL-6 and IL-1 synergistically enhanced
the production of MMPs from synovial cells by
up-regulating IL-6 production and IL-1 receptor I
expression. Cytokine 51, 178–183
99 Silacci, P., Dayer, J. M., Desgeorges, A., Peter, R.,
Manueddu, C. and Guerne, P. A. (1998) Interleukin (IL)-6
and its soluble receptor induce TIMP-1 expression in
synoviocytes and chondrocytes, and block IL-1-induced
collagenolytic activity. J. Biol. Chem. 273, 13625–13629
100 Garnero, P., Thompson, E., Woodworth, T. and Smolen,
J. S. (2010) Rapid and sustained improvement in bone and
cartilage turnover markers with the anti-interleukin-6
receptor inhibitor tocilizumab plus methotrexate in
rheumatoid arthritis patients with an inadequate response
to methotrexate: results from a substudy of the
multicenter double-blind, placebo-controlled trial of
tocilizumab in inadequate responders to methotrexate
alone. Arthritis Rheum. 62, 33–43
101 Uchiyama, Y., Koike, N. and Mihara, M. (2009) Anemia
in monkey collagen-induced arthritis is correlated with
serum IL-6, but not TNFα. Rheumatol. Int. 28, 879–883
102 Ganz, T. (2003) Hepcidin, a key regulator of iron
metabolism and mediator of anemia of inflammation.
Blood 102, 783–788
103 Rivera, S., Nemeth, E., Gabayan, V., Lopez, M. A.,
Farshidi, D. and Ganz, T. (2005) Synthetic hepcidin causes
rapid dose-dependent hypoferremia and is concentrated
in ferroportin-containing organs. Blood 106, 2196–2199
104 Nicolas, G., Bennoun, M., Porteu, A., Mativet, S.,
Beaumont, C., Grandchamp, B., Sirito, M., Sawadogo, M.,
Kahn, A. and Vaulont, S. (2002) Severe iron deficiency
anemia in transgenic mice expressing liver hepcidin. Proc.
Natl. Acad. Sci. U.S.A. 99, 4596–4601
105 Nemeth, E., Rivera, S., Gabayan, V., Keller, C., Taudorf,
S., Pedersen, B. K. and Ganz, T. (2004) IL-6 mediates
hypoferremia of inflammation by inducing the synthesis
of the iron regulatory hormone hepcidin. J. Clin. Invest.
113, 1271–1276
106 Hashizume, M., Uchiyama, Y., Horai, N., Tomosugi, N.
and Mihara, M. (2010) Tocilizumab, a humanized
anti-interleukin-6 receptor antibody, improved anemia in
monkey arthritis by suppressing IL-6-induced hepcidin
production. Rheumatol. Int. 30, 917–923
107 Song, S. N., Tomosugi, N., Kawabata, H., Ishikawa, T.,
Nishikawa, T. and Yoshizaki, K. (2010) Down-regulation
of hepcidin resulting from long-term treatment with an
anti-IL-6 receptor antibody (tocilizumab) improves
anemia of inflammation in multicentric Castleman
disease. Blood 116, 3627–3634
108 Katsume, A., Saito, H., Yamada, Y., Yorozu, K., Ueda, O.,
Akamatsu, K., Nishimoto, N., Kishimoto, T., Yoshizaki,
K. and Ohsugi, Y. (2002) Anti-interleukin 6 (IL-6)
receptor antibody suppresses Castleman’s disease like
symptoms emerged in IL-6 transgenic mice. Cytokine 20,
304–311
IL-6 signalling and its biological activities
109 Wallenius, V., Wallenius, K., Ahren, B., Rudling, M.,
Carlsten, H., Dickson, S. L., Ohlsson, C. and Jansson, J.
O. (2002) Interleukin-6-deficient mice develop
mature-onset obesity. Nat. Med. 8, 75–79
110 Yoshizaki, K., Matsuda, T., Nishimoto, N., Kuritani, T.,
Taeho, L., Aozasa, K., Nakahata, T., Kawai, H., Tagoh, H.
and Komori, T. (1989) Pathogenic significance of
interleukin-6 (IL-6/BSF-2) in Castleman’s disease. Blood
74, 1360–1367
111 Nishimoto, N., Kanakura, Y., Aozasa, K., Johkoh, T.,
Nakamura, M., Nakano, S., Nakano, N., Ikeda, Y., Sasaki,
T., Nishioka, K. et al. (2005) Humanized
anti-interleukin-6 receptor antibody treatment of
multicentric Castleman disease. Blood 106, 2627–2632
112 Myasoedova, E., Crowson, C. S., Kremers, H. M.,
Fitz-Gibbon, P. D., Therneau, T. M. and Gabriel, S. E.
(2010) Total cholesterol and LDL levels decrease before
rheumatoid arthritis. Ann. Rheum. Dis. 69, 1310–1314
113 Hashizume, M., Yoshida, H., Koike, N., Suzuki, M. and
Mihara, M. (2010) Overproduced interleukin 6 decreases
blood lipid levels via upregulation of very-low-density
lipoprotein receptor. Ann. Rheum. Dis. 69, 741–746
114 Sopasakis, V. R., Sandqvist, M., Gustafson, B.,
Hammarstedt, A., Schmelz, M., Yang, X., Jansson, P. A.
and Smith, U. (2004) High local concentrations and
effects on differentiation implicate interleukin-6 as a
paracrine regulator. Obes. Res. 12, 454–460
115 Trujillo, M. E., Sullivan, S., Harten, I., Schneider, S. H.,
Greenberg, A. S. and Fried, S. K. (2004) Interleukin-6
regulates human adipose tissue lipid metabolism and
leptin production in vitro. J. Clin. Endocrinol. Metab. 89,
5577–5582
116 Petersen, E. W., Carey, A. L., Sacchetti, M., Steinberg, G.
R., Macaulay, S. L., Febbraio, M. A. and Pedersen, B. K.
(2005) Acute IL-6 treatment increases fatty acid turnover
in elderly humans in vivo and in tissue culture in vitro.
Am. J. Physiol. Endocrinol. Metab. 288, E155–E162
117 van Hall, G., Steensberg, A., Sacchetti, M., Fischer, C.,
Keller, C., Schjerling, P., Hiscock, N., Moller, K., Saltin,
B., Febbraio, M. A. and Pedersen, B. K. (2003)
Interleukin-6 stimulates lipolysis and fat oxidation in
humans. J. Clin. Endocrinol. Metab. 88, 3005–3010
118 Schoonjans, K., Staels, B. and Auwerx, J. (1996) Role of
the peroxisome proliferator-activated receptor (PPAR) in
mediating the effects of fibrates and fatty acids on gene
expression. J. Lipid Res. 37, 907–925
119 Patel, D. D., Knight, B. L., Wiggins, D., Humphreys, S.
M. and Gibbons, G. F. (2001) Disturbances in the normal
regulation of SREBP-sensitive genes in PPARα-deficient
mice. J. Lipid Res. 42, 328–337
120 Horton, J. D., Goldstein, J. L. and Brown, M. S. (2002)
SREBPs: activators of the complete program of
cholesterol and fatty acid synthesis in the liver. J. Clin.
Invest. 109, 1125–1131
121 Shimomura, I., Bashmakov, Y. and Horton, J. D. (1999)
Increased levels of nuclear SREBP-1c associated with
fatty livers in two mouse models of diabetes mellitus. J.
Biol. Chem. 274, 30028–30032
122 Hashizume, M. and Mihara, M. (2011) IL-6 and lipid
metabolism. Inflammation Regener. 31, 325–333
123 Nishimoto, N., Yoshizaki, K., Miyasaka, N., Yamamoto,
K., Kawai, S., Takeuchi, T., Hashimoto, J., Azuma, J. and
Kishimoto, T. (2004) Treatment of rheumatoid arthritis
with humanized anti-interleukin-6 receptor antibody: a
multicenter, double-blind, placebo-controlled trial.
Arthritis Rheum. 50, 1761–1766
124 Saiki, O., Takao, R., Naruse, Y., Kuhara, M., Imai, S. and
Uda, H. (2007) Infliximab but not methotrexate induces
extra-high levels of VLDL-triglyceride in patients with
rheumatoid arthritis. J. Rheumatol. 34, 1997–2004
125 Choi, H. K. and Seeger, J. D. (2005) Lipid profiles among
US elderly with untreated rheumatoid arthritis: the Third
National Health and Nutrition Examination Survey. J.
Rheumatol. 32, 2311–2316
126 Park, Y. B., Choi, H. K., Kim, M. Y., Lee, W. K., Song, J.,
Kim, D. K. and Lee, SK. (2002) Effects of antirheumatic
therapy on serum lipid levels in patients with rheumatoid
arthritis: a prospective study. Am. J. Med. 113, 188–193
127 Seriolo, B., Paolino, S., Sulli, A., Fasciolo, D. and Cutolo,
M. (2006) Effects of anti-TNF-α treatment on lipid
profile in patients with active rheumatoid arthritis. Ann.
NY Acad. Sci. 1069, 414–419
128 Kawashiri, S. Y., Kawakami, A., Yamasaki, S., Imazato, T.,
Iwamoto, N., Fujikawa, K., Aramaki, T., Tamai, M.,
Nakamura, H., Ida, H. et al. (2011) Effects of the
anti-interleukin-6 receptor antibody, tocilizumab, on
serum lipid levels in patients with rheumatoid arthritis.
Rheumatol. Int. 31, 451–456
129 Yokoe, T., Iino, Y., Takei, H., Horiguchi, J., Koibuchi, Y.,
Maemura, M., Ohwada, S. and Morishita, Y. (1997)
Changes of cytokines and thyroid function in patients
with recurrent breast cancer. Anticancer Res. 17, 695–699
130 Goydos, J. S., Brumfield, A. M., Frezza, E., Booth, A.,
Lotze, M. T. and Carty, S. E. (1998) Marked elevation of
serum interleukin-6 in patients with cholangiocarcinoma:
validation of utility as a clinical marker. Ann. Surg. 227,
398–404
131 Adler, H. L., McCurdy, M. A., Kattan, M. W., Timme, T.
L., Scardino, P. T. and Thompson, T. C. (1999) Elevated
levels of circulating interleukin-6 and transforming
growth factor-β1 in patients with metastatic prostatic
carcinoma. J. Urol. 161, 182–187
132 Kallio, J. P., Tammela, T. L., Marttinen, A. T. and
Kellokumpu-Lehtinen, P. L. (2001) Soluble
immunological parameters and early prognosis of renal
cell cancer patients. J. Exp. Clin. Cancer Res. 20, 523–528
133 Lee, S. O., Chun, J. Y., Nadiminty, N., Lou, W. and Gao,
A. C. (2007) Interleukin-6 undergoes transition from
growth inhibitor associated with neuroendocrine
differentiation to stimulator accompanied by androgen
receptor activation during LNCaP prostate cancer cell
progression. Prostate 67, 764–773
134 Ara, T., Song, L., Shimada, H., Keshelava, N., Russell, H.
V., Metelitsa, L. S., Groshen, S. G., Seeger, R. C. and
DeClerck, Y. A. (2009) Interleukin-6 in the bone marrow
microenvironment promotes the growth and survival of
neuroblastoma cells. Cancer Res. 69, 329–337
135 Ogata, A., Chauhan, D., Teoh, G., Treon, S. P., Urashima,
M., Schlossman, R. L. and Anderson, K. C. (1997) IL-6
triggers cell growth via the Ras-dependent
mitogen-activated protein kinase cascade. J. Immunol.
159, 2212–2221
136 Smith, P. C., Hobisch, A., Lin, D. L., Culig, Z. and Keller,
E. T. (2001) Interleukin-6 and prostate cancer
progression. Cytokine Growth Factor Rev. 12, 33–40
137 Miki, S., Iwano, M., Miki, Y., Yamamoto, M., Tang, B.,
Yokokawa, K., Sonoda, T., Hirano, T. and Kishimoto, T.
(1989) Interleukin-6 (IL-6) functions as an in vitro
autocrine growth factor in renal cell carcinomas. FEBS
Lett. 250, 607–610
138 Cavarretta, I. T., Neuwirt, H., Untergasser, G., Moser, P.
L., Zaki, M. H., Steiner, H., Rumpold, H., Fuchs, D.,
Hobisch, A., Nemeth, J. A. and Culig, Z. (2007) The
antiapoptotic effect of IL-6 autocrine loop in a cellular
model of advanced prostate cancer is mediated by Mcl-1.
Oncogene 26, 2822–2832
139 Weidle, U. H., Klostermann, S., Eggle, D. and Krüger, A.
(2010) Interleukin 6/interleukin 6 receptor interaction and
its role as a therapeutic target for treatment of cachexia
and cancer. Cancer Genomics Proteomics 7, 287–302
140 Ara, T. and Declerck, Y. A. (2010) Interleukin-6 in bone
metastasis and cancer progression. Eur. J. Cancer 46,
1223–1231
141 Kawano, M., Hirano, T., Matsuda, T., Taga, T., Horii, Y.,
Iwato, K., Asaoku, H., Tang, B., Tanabe, O., Tanaka, H.
et al. (1988) Autocrine generation and requirement of
BSF-2/IL-6 for human multiple myelomas. Nature 332,
83–85
142 Klein, B., Zhang, X. G., Jourdan, M., Content, J.,
Houssiau, F., Aarden, L., Piechaczyk, M. and Bataille, R.
(1989) Paracrine rather than autocrine regulation of
myeloma-cell growth and differentiation by
interleukin-6. Blood 73, 517–526
143 Schwarze, M. M. and Hawley, R. G. (1995) Prevention of
myeloma cell apoptosis by ectopic bcl-2 expression or
interleukin 6-mediated up-regulation of bcl-xL. Cancer
Res. 55, 2262–2265
C
The Authors Journal compilation
C
2012 Biochemical Society
157
158
M. Mihara and others
144 Keller, E. T., Wanagat, J. and Ershler, W. B. (1996)
Molecular and cellular biology of interleukin-6 and its
receptor. Front. Biosci. 1, d340–d357
145 Dutt, S. S. and Gao, A. C. (2009) Molecular mechanisms
of castration-resistant prostate cancer progression. Future
Oncol. 5, 1403–1413
146 Chung, T. D., Yu, J. J., Kong, T. A, Spiotto, M. T. and Lin,
J. M. (2000) Interleukin-6 activates phosphatidylinositol3 kinase, which inhibits apoptosis in human prostate
cancer cell lines. Prostate 42, 1–7
147 Loprinzi, C. L., Ellison, N. M., Goldberg, R. M.,
Michalak, J. C. and Burch, P. A. (1990) Alleviation of
cancer anorexia and cachexia: studies of the Mayo Clinic
and the North Central Cancer Treatment Group. Semin.
Oncol. 17, 8–12
148 Bachmann, J., Heiligensetzer, M., Krakowski-Roosen, H.,
Büchler, M. W., Friess, H. and Martignoni, M. E. (2008)
Cachexia worsens prognosis in patients with resectable
pancreatic cancer. J. Gastrointest. Surg. 12, 1193–1201
149 Carson, J. A. and Baltgalvis, K. A. (2010) Interleukin 6 as
a key regulator of muscle mass during cachexia. Exercise
Sport Sci. Rev. 38, 168–176
150 Fujimoto-Ouchi, K., Tamura, S., Mori, K., Tanaka, Y. and
Ishitsuka, H. (1995) Establishment and characterization
of cachexia-inducing and -non-inducing clones of murine
colon 26 carcinoma. Int. J. Cancer. 61, 522–528
151 Ohe, Y., Podack, E. R., Olsen, K. J., Miyahara, Y., Miura,
K., Saito, H., Koishihara, Y., Ohsugi, Y., Ohira, T.,
Nishio, K. and Saijo, N. (1993) Interleukin-6 cDNA
transfected Lewis lung carcinoma cells show unaltered net
tumour growth rate but cause weight loss and shortened
survival in syngeneic mice. Br. J. Cancer. 67, 939–944
152 Rigas, J. R., Schuster, M., Orlov, S. V., Milovanovic, B.,
Prabhash, B. K., Smith, J. T. and the ALD518 study
group. (2010) Effect of ALD518, a humanized anti-IL-6
antibody, on lean body mass loss and symptoms in
patients with advanced non-small cell lung cancer
(NSCLC): results of a phase II randomized, double-blind
safety and efficacy trial. J. Clin. Oncol. 28 (Suppl. 15)
A7622
153 Schuster, M., Rigas, J. R., Orlov, S. V., Milovanovic, B.,
Prabhash, K., Smith, J. T. and the ALD518 study group.
(2010) ALD518, a humanized anti-IL-6 antibody, treats
anemia in patients with advanced non-small cell lung
cancer (NSCLC): results of a phase II, randomized,
double-blind, placebo-controlled trial. J. Clin. Oncol. 28
(Suppl. 15) A7631
154 Grivennikov, S., Karin, E., Terzic, J., Mucida, D., Yu, G.
Y., Vallabhapurapu, S., Scheller, J., Rose-John, S.,
Cheroutre, H., Eckmann, L. and Karin, M. (2009) IL-6
and Stat3 are required for survival of intestinal epithelial
cells and development of colitis-associated cancer. Cancer
Cell 15, 103–113
155 Schiechl, G., Bauer, B., Fuss, I., Lang, S. A., Moser, C.,
Ruemmele, P., Rose-John, S., Neurath, M. F., Geissler, E.
K., Schlitt, H. J. et al. (2011) Tumor development in
murine ulcerative colitis depends on MyD88 signaling of
colonic F4/80 + CD11bhigh Gr1low macrophages. J. Clin.
Invest. 121, 1692–1708
156 Mihara, M., Kasutani, K., Okazaki, M., Nakamura, A.,
Kawai, S., Sugimoto, M., Matsumoto, Y. and Ohsugi, Y.
(2005) Tocilizumab inhibits signal transduction mediated
by both mIL-6R and sIL-6R, but not by the receptors of
other members of IL-6 cytokine family. Int.
Immunopharmacol. 5, 1731–1740
157 Nishimoto, N., Sasai, M., Shima, Y., Nakagawa, M.,
Matsumoto, T., Shirai, T., Kishimoto, T. and Yoshizaki, K.
(2000) Improvement in Castleman’s disease by humanized
anti-interleukin-6 receptor antibody therapy. Blood 95,
56–61
158 Hirano, T., Matsuda, T., Turner, M., Miyasaka, N.,
Buchan, G., Tang, B., Sato, K., Shimizu, M., Maini, R.,
Feldmann, M. and Kishimoto, T. (1988) Excessive
production of interleukin 6/B cell stimulatory factor-2 in
rheumatoid arthritis. Eur. J. Immunol. 18, 1797–1801
C
The Authors Journal compilation
C
2012 Biochemical Society
159 Madhok, R., Crilly, A., Watson, J. and Capell, H. A.
(1993) Serum interleukin 6 levels in rheumatoid arthritis:
correlations with clinical and laboratory indices of disease
activity. Ann. Rheum. Dis. 52, 232–234
160 Nishimoto, N., Miyasaka, N., Yamamoto, K., Kawai, S.,
Takeuchi, T., Azuma, J. and Kishimoto, T. (2009) Study of
active controlled tocilizumab monotherapy for
rheumatoid arthritis patients with an inadequate response
to methotrexate (SATORI): significant reduction in
disease activity and serum vascular endothelial growth
factor by IL-6 receptor inhibition therapy. Mod.
Rheumatol. 19, 12–19
161 Jones, G., Sebba, A., Gu, J., Lowenstein, M. B., Calvo, A.,
Gomez-Reino, J. J., Siri, D. A., Tomsic, M., Alecock, E.,
Woodworth, T. and Genovese, M. C. (2010) Comparison
of tocilizumab monotherapy versus methotrexate
monotherapy in patients with moderate to severe
rheumatoid arthritis: the AMBITION study. Ann.
Rheum. Dis. 69, 88–96
162 Genovese, M. C., McKay, J. D., Nasonov, E. L., Mysler,
E. F., da Silva, N. A., Alecock, E., Woodworth, T. and
Gomez-Reino, J. J. (2008) Interleukin-6 receptor
inhibition with tocilizumab reduces disease activity in
rheumatoid arthritis with inadequate response to
disease-modifying antirheumatic drugs: the tocilizumab
in combination with traditional disease-modifying
antirheumatic drug therapy study. Arthritis Rheum. 58,
2968–2980
163 Smolen, J. S., Beaulieu, A., Rubbert-Roth, A.,
Ramos-Remus, C., Rovensky, J., Alecock, E.,
Woodworth, T. and Alten, R. (2008) Effect of
interleukin-6 receptor inhibition with tocilizumab in
patients with rheumatoid arthritis (OPTION study): a
double-blind, placebo-controlled, randomised trial.
Lancet 371, 987–997
164 Kremer, J. M., Blanco, R., Brzosko, M., Burgos-Vargas,
R., Halland, A. M., Vernon, E., Ambs, P. and Fleischmann,
R. (2011) Tocilizumab inhibits structural joint damage in
rheumatoid arthritis patients with inadequate responses to
methotrexate: results from the double-blind treatment
phase of a randomized placebo-controlled trial of
tocilizumab safety and prevention of structural joint
damage at one year. Arthritis Rheum. 63, 609–621
165 Emery, P., Keystone, E., Tony, H. P., Cantagrel, A., van
Vollenhoven, R., Sanchez, A., Alecock, E., Lee, J. and
Kremer, J. (2008) IL-6 receptor inhibition with
tocilizumab improves treatment outcomes in patients
with rheumatoid arthritis refractory to anti-tumour
necrosis factor biologicals: results from a 24-week
multicentre randomised placebo-controlled trial. Ann.
Rheum. Dis. 67, 1516–1523
166 De Benedetti, F., Pignatti, P., Gerioni, V., Massa, M.,
Sartirana, P., Caporali, R., Montecucco, C. M., Corti, A.,
Fantini, F. and Martini, A. (1997) Differences in synovial
fluid cytokine levels between juvenile and adult
rheumatoid arthritis. J. Rheumatol. 24, 1403–1409
167 Romanovsky, A. A., Almeida, M. C., Aronoff, D. M.,
Ivanov, A. I., Konsman, J. P., Steiner, A. A. and Turek,
V. F. (2005) Fever and hypothermia in systemic
inflammation: recent discoveries and revisions. Front.
Biosci. 10, 2193–2216
168 Yokota, S., Imagawa, T., Mori, M., Miyamae, T., Aihara,
Y., Takei, S., Iwata, N., Umebayashi, H., Murata, T.,
Miyoshi, M. et al. (2008) Efficacy and safety of
tocilizumab in patients with systemic-onset juvenile
idiopathic arthritis: a randomised, double-blind,
placebo-controlled, withdrawal phase III trial. Lancet
371, 998–1006
169 De Benedetti, F., Brunner, H., Ruperto, N., Wright, S.,
Kenwright, A., Cuttica, R., Woo, P., Schneider, R., Lovell,
D. and Martini, A. (2010) Efficacy and safety of
tocilizumab in patients with systemic juvenile idiopathic
arthritis (sJIA): 12-week data from the phase 3 TENDER
trial. Ann. Rheum. Dis. 69 (Suppl. 3), 146
170 Tanaka, T., Narazaki, M. and Kishimoto, T. (2011)
Anti-interleukin-6 receptor antibody, tocilizumab, for the
treatment of autoimmune diseases. FEBS Lett.,
doi:10.1016/j.febslet.2011.03.023
IL-6 signalling and its biological activities
171 Kopf, M., Bachmann, M. F. and Marsland, B. J. (2010)
Averting inflammation by targeting the cytokine
environment. Nat. Rev. Drug Discovery 9, 703–718
172 Nishimoto, N. (2010) Interleukin-6 as a therapeutic target
in candidate inflammatory diseases. Clin. Pharmacol.
Ther. 87, 483–487
Received 28 June 2011/15 August 2011; accepted 1 September 2011
Published on the Internet 14 October 2011, doi:10.1042/CS20110340
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2012 Biochemical Society
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