ISSN 00268933, Molecular Biology, 2015, Vol. 49, No. 6, pp. 837–842. © Pleiades Publishing, Inc., 2015.

Original Russian Text © M.S. Drutskaya, M.A. Nosenko, K.S.N. Atretkhany, G.A. Efimov, S.A. Nedospasov, 2015, published in Molekulyarnaya Biologiya, 2015, Vol. 49, No. 6,
pp. 937–943.

REVIEWS
UDC 577

Interleukin6: From Molecular Mechanisms of Signal Transduction

to Physiological Properties and Therapeutic Targeting1
M. S. Drutskayaa, M. A. Nosenkoa, b, K.S. N. Atretkhanya, b, G. A. Efimova, c, and S. A. Nedospasova, b
a
Engelhardt Institute of Molecular Biology Russian Academy of Sciences, Moscow, 119991 Russia;
email: marinadru@gmail.com
b
Department of Biology, Moscow State University, Moscow, 119991 Russia
cNational Research Center for Hematology, Moscow, 125167 Russia

Received July 23, 2015; in final form, July 23, 2015

Abstract—Interleukin6 (IL6) is one of the most important proinflammatory cytokines that has a broad
spectrum of immunoregulatory properties. The molecular mechanisms of signal transduction of IL6 and its
receptor, which have been previously established, were later supplemented with a concept of transsignaling.
The selective inhibition of this signaling cascade would allow the modulation of the pathological effects of IL6.
Reverse genetics methods helped to establish the physiological functions of IL6 in normal state and in vari
ous diseases, including neoplasias. Therapeutic inhibitors of IL6 or its receptor are already used to treat sev
eral autoimmune diseases; however, the systemic inhibition inevitably also neutralizes the protective func
tions of this cytokine. It is expected that, in the future, systemic therapy will be replaced by more specific and
effective approaches that take into account the peculiarities of molecular signaling pathways in target cells
and differences in the function of IL6 depending on the cell source.
DOI: 10.1134/S0026893315060060
Keywords: proinflammatory cytokines, interleukin 6, IL6, IL6R, gp130, chronic inflammation, anticytok
ine therapy, transsignaling

Interleukin6 is a proinflammatory cytokine with a contributed to formulation of some general paradigms

wide spectrum of immunoregulatory properties. It also
mediates the formation, growth and progression of
tumors of different origin and localization. Studies of the
mechanisms of IL6 dependent intracellular signal trans
duction helped to establish many of the general princi
ples of cytokine action. The phenotype of mice deficient
in IL6 or its receptor suggests some nonredundant
functions of this signaling cascade, in particular in host
protection against infections. Reverse genetics methods
have recently provided more accurate physiological
models to address the role of the IL6/IL6R axis. Using
these models, we will attempt to answer a legitimate
question on whether systemic IL6 blockade will also
inevitably neutralize the beneficial properties of IL6 and
result in adverse side effects. We suggest that antiIL6
therapy can be made more specific and effective if,
instead of a systemic neutralization approach, only a por
tion of biologically active cytokine coming from the main
pathogenic cell sources or only IL6 involved in trans
signaling cascade will be selectively blocked.
INTERLEUKIN6 INTRACELLULAR
SIGNALING
The molecular mechanism of signal transduction
of IL6/IL6R was described over 20 years ago [1] and
1 ferent set of activated genes. It was initially thought
The article was translated by the authors.
in the cytokine field. IL6 binds to a cell surface recep
tor subunit IL6R, which, first, is expressed only in
certain cell types, and second, it is not able to transmit
an intracellular signal by itself. The signaling subunit is
a transmembrane glycoprotein, gp130, common to
many members of the IL6 family, namely: IL11, IL27,
oncostatin, LIF, cardiotrophin 1. Upon the interac
tion of IL6–IL6R complex with gp130 dimerization
of the latter occurs, which in turn, recruits and acti
vates the JAK family tyrosine kinases. Activated JAK
kinases phosphorylate gp130, as well as contribute to
recruitment and further phosphorylation of STAT
family proteins, such as STAT1 and STAT3 (Fig. 1a).
Phosphorylated STATs are then released from the
complex with gp130, dimerize and translocate to the
nucleus.
This is followed by activation of the transcription of
a large number of genes that contain STATbinding
motifs in their regulatory regions. Furthermore, a neg
ative feedback loop is formed upon activation of STAT
inhibitors, such as SOCS3 and PIAS. Activated JAK
kinases also phosphorylate SH2, which, in turn, acti
vates GTPase Ras and induces MAPKcascade that
controls cell proliferation and differentiation. In fact,
all effects of IL6/IL6R signal transduction on cells
result from additive functions of target genes in a spe
cific cell type so that different cells will possess a dif

837
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that cells that do not express IL6R are not able to
respond to IL6. However, it turned out that there is
also an alternative signaling cascade, i.e., socalled
transsignaling, which is mediated by the soluble form
of IL6 receptor (sIL6R), which is either produced as
a result of proteolytic cleavage from the cell surface by
metalloproteinases or alternative splicing (Fig. 1b).
The IL6–sIL6R complex is able to induce the
homodimerization of gp130 in cells, which do not
express IL6R, thereby significantly extending the
range of possible targets of this cytokine (gp130 is
expressed in a wide variety of cells and is not limited to
cells of the immune system).
Importantly, in the case of other proinflammatory
cytokines, such as TNF or IL1, which bind to the sol
uble receptor, and, thus, initiate the negative feedback
mechanism, since the soluble form of these receptors
acts as an antagonist by competing for the cytokine. It
should also be pointed out that, in an IL6dependent
cascade, the role of the transsignaling inhibitor is played
by the soluble form of gp130, i.e., sgp130 (Fig. 1b).
PHYSIOLOGICAL AND PATHOLOGICAL
PROPERTIES OF IL6 ESTABLISHED
BY THE METHODS OF REVERSE GENETICS
In recent years, the two main questions relating to
IL6 biology have been the focus of many studies.
First, the molecular basis of immune regulation medi
ated by this cytokine and, second, the molecular
mechanisms of IL6 involvement in tumorigenesis
and chronic inflammationassociated with the devel
opment of certain types of cancer [2, 3]. It has been
shown that IL6 production by Tlymphocytes is nec
essary for their differentiation into several key popula
tions of T helper cells, such as Th17 and follicular T
helpers (Tfh) [4]. Moreover, stromal cells can serve as
the source of immunomodulatory IL6 [5].
Essential insight into the physiological functions of
IL6 in normal state and in pathology can be obtained
by using reverse genetics approach in mice. In line
with this, mice with complete or tissuespecific abla
tion of IL6 have been generated (Fig. 2a) [6]. Studies
using these mice established an important role of IL6
in the development of experimental autoimmune
encephalomyelitis (EAE)—a mouse model of multi
ple sclerosis. Mice with complete IL6 inactivation are
resistant to EAE [7], suggesting a pathogenic role for
this cytokine in this disease model. It was found that
IL6 produced by T cells is not involved in passive
EAE induction caused by adaptive transfer of patho
genic T cells [8]. However, adaptive transfer of mye
loid dendritic cells into IL6deficient hosts turned
them susceptible to the development of EAE. This
indicates that IL6 from dendritic cells is sufficient to
induce development of pathogenic T cells [8]. The role
of interleukin6, produced by B cells, in the induction
of EAE was also addressed by several independent
groups, but the results are somewhat controversial and
need to be further elucidated [9, 10].
In addition, the role of IL6 in the development of
antigeninduced arthritis has also been investigated.
The results showed that, along with the control of cel
lular and humoral components of the immune
response, IL6 is also involved in the induction of the
onset of chronic type of the disease, apparently via the
regulation of osteoclast precursors [11, 12]. A number
of studies have been aimed at elucidating the possible
molecular mechanisms of rheumatoid arthritis inhibi
tion. It has been shown that an IL6R blockade causes
the expansion of specific population of regulatory
T cells in patients suffering from rheumatoid arthritis,
as well as in mice during collageninduced arthritis
[13]. Even though there is sufficient data suggesting
that IL6 mediates the development of arthritis, the
contribution of each specific cell type remains unclear
and needs to be established. The increased production
of IL6 is also associated with various lung patholo
gies, such as asthma or chronic obstructive pulmonary
disease, which suggests the involvement of this cytok
ine in the pathogenesis of these diseases [14–16].
Previously, the role of IL6 has been investigated in
tumorigenesis. Mice with complete IL6 ablation were
more resistant to the development of colitisassociated
colon cancer [3, 17, 18]. These results correlate with
the increased incidence of colon cancer in mice char
acterized by overexpression of STAT3 in intestinal epi
thelial cells, and, on the contrary, with the increased
resistance to the development of colon cancer in mice
characterized by tissue specific inactivation of STAT3
in enterocytes [3, 19, 20]. Preliminary data obtained in
vitro on several cell lines suggests that IL6 may play a
role in the development of squamous cell carcinoma [21].
INTERLEUKIN6 AND ITS RECEPTOR
AS THERAPEUTIC TARGETS
Interleukin6 is one of the most important and
beststudied cytokines has a number of nonredun
dant functions that were established using reverse
genetics approach. Nevertheless, it is also one of the
targets for successful systemic anticytokine therapy.
Tocilizumab, which is a humanized antibody against
IL6R (Fig. 3a), is approved for treating rheumatoid

Fig. 1. Scheme of the IL6/IL6R signaling cascade. (a) Classicsignaling pathway is carried out by IL6 interacting with mem
branebound form of the receptor, i.e., IL6R. (b) Alternative signaling pathway, or transsignaling. The soluble form of the recep
tor (sIL6R) is formed by alternative splicing or proteolytic cleavage of the receptor transmebrane domain by metalloproteases
ADAM17, ADAM10, Cathepsin G, or SMP. Soluble sIL6R–IL6 complex interacts with gp130 molecule, which is expressed
by many cell types. Furthermore, there is a soluble form of gp130 molecule (sgp130), which acts as an antagonist by binding the
soluble sIL6R–IL6 complex and inhibiting the transsignaling pathway.

MOLECULAR BIOLOGY Vol. 49 No. 6 2015