Document 6423438

Archives of Perinatal Medicine 19(3), 145-149, 2013
ORIGINAL PAPER
The complex role of Il-6 in physiology and pathology
MAGDALENA DUTSCH-WICHEREK1,2, WOJCIECH KAŹMIERCZAK2,3, URSZULA GRĘŹLIKOWSKA4,5
Abstract
The study briefly reviews the biological role of IL-6 in various physiological and pathological situations. IL-6 participates in the broad spectrum of biological processes such as immune responses, oncogenesis, in pregnancy
it enables the maintenance of the balance between immunoregulatory activity of the placenta, maternal immune
system and fetal immune system, finally co-creating the phenomenon of the immune tolerance during pregnancy.
The deregulation of IL-6 production and expression of IL-6 membrane and soluble receptors results in various
pathologies such as immune mediated diseases, chronic inflammations, recurrent miscarriages, preeclampsia,
preterm birth, malignant neoplasms including multiple myeloma, ovarian cancer and others. The biological activity
of IL-6 is determined by the tumor microenvironment. The future understanding of the complex regulation of the
biological activity of this cytokine might provide the new therapeutic strategies in various inflammatory and neoplasmatic diseases.
Key words: Immune tolerance, cancer microenvironment, IL-6
Introduction
Interleukin-6 (IL-6) is a pleiotropic cytokine with
a wide range of biological activities in the immune regulation, hematopoiesis, inflammation, and oncogenesis
[1-3]. IL-6 was shown to be produced by T-cells, B-cells,
monocytes, fibroblasts, endothelial cells and several
kinds of tumor cells. This cytokine has also a wide range
of biological activities on various target cells. IL-6 is
a differentiation factor for B-cells, T-cells and macrophages, differentiates the megakaryocytes to produce platelets and hematopoietic stem cells [4, 5]. IL-6 stimulates hepatocytes to produce acute phase proteins such
as C-reactive protein (CRP), fibrinogen, α1-antitrypsin
and serum amyloid A (SAA), and suppresses the production of albumin. IL-6 introduced in vivo induces leukocytosis fever. IL-6 is also a growth factor for mesangial
cells, various tumor cells including lymphoma cells,
multiple myeloma cells and Kaposi sarcoma cells [2, 3].
This cytokine plays an important role in the etiology of
various pathological conditions as inflammatory, autoimmunity and malignant diseases [2].
The IL-6 receptor system consists of two functional
membrane proteins: an 80 kDa ligand binding chain
1
(IL-6R) and a 130kDa (known also as gp130) non-ligand
binding chain acting as a signal transducing chain. Activation of gp130 activates members of Janus kinases
(JAK) family, the signal transducers and activators of
the transcription-3 (STAT3) pathway, and the CCAAT/
enhancer binding protein (C/EBP) pathway [6]. IL-6 can
induce STAT1 with the balance STAT1 and STAT3 signals influenced by the microenvironment and costimulation by IFNγ and Toll-like receptor-4 (TLR4) ligands,
which changes the balance towards STAT1 and inhibits
STAT3 [7]. The distribution of IL-6R and gp130 among
the cells is different, gp130 is identified in almost all
cells, while IL-6R expression is observed in hepatocytes
and leucocytes [8, 9]. The biological activity of IL-6 is
determined also by the distribution of the soluble form
of IL-6R (sIL6-R). This receptor forms a complex with
IL-6 that binds cell surface gp130 to induce the response, the regulation of this process is named IL-6 transsignaling [8]. IL-6 trans-signaling can be inhibited by
a soluble form of gp130, by competing with membranebound gp130 for IL-6/IL-6R complexes [10, 11].
Overproduction of IL-6 is observed in various inflammatory diseases, such as rheumatoid arthritis where it
Laryngology Outpatients Unit, Lukaszczyk Oncological Center, Bydgoszcz
Department of Otolaryngology and Oncological Laryngology with Subdivision of Audiology and Phoniatry, Jurasz’s University
Hospital, Bydgoszcz
3
Department of Pathophysiology of Hearing and Balance System, Ludwik Rydygier’s Collegium Medicum, Nicolaus Copernicus
University, Bydgoszcz
4
Department of Gynecology and Oncology, Lukaszczyk Oncological Center, Bydgoszcz
5
Chair of Gynecology, Oncology, and Gynecological Nursing, Ludwik Rydygier Collegium Medicum, Nicolaus Copernicus
University, Bydgoszcz
2
146
M. Dutsch-Wicherek,, W. Kaźmierczak, U. Gręźlikowska
is produced by synovial tissues of the joints, in Castelman’s disease with the symptoms of fever, lymph nodes
enlargement, anemia, high levels of acute phase proteins. In such pathological conditions the high IL-6 levels
were accompanied by high soluble IL-6R levels. In order
to block the signal transducing for the treatment of
these diseases, an antibody against the receptors, a humanized anti-IL-6R antibody was prepared (tocilizumab).
The results of the treatment with tocilizumab in various
immune mediated diseases including reactive arthritis,
juvenile idiopathic arthritis, rheumatoid arthritis, Castelman’s disease were very promising and are under continuous investigations [2, 12].
IL-6 and reproductive tract
The IL-6 production remains also under hormonal
influence, for example hormones including oestrogen
and testosterone seem to inhibit the secretion of IL-6,
and this has been proposed to be the reason of increased
circulating IL-6 following menopause and andropause
[13]. Moreover, IL-6 participates in the early pregnancy,
from the peri-conceptual period. IL-6 is produced by
luminal and glandular epithelial cells in the proliferative
cycle phase with the strongest expression in the epithelium and the stroma in mid-secretory cycle phase at
the time of implantation. The menstrual cycle-dependent
expression of IL-6 suggests that this cytokine may play
a role in changes in endometrium that prepare this
tissue for implantation and menstrual shedding [14]. In
vitro studies revealed that IL-6 can promote the preimplantation embryo development and increase blastocyst
cell number [15]. IL-6 seems to control trophoblast/placenta cells invasiveness depending on the differentiation
stage of pregnancy growth [16, 17]. IL-6 protein and
mRNA are observed to be expressed in decidual tissue
and placenta over the course of gestation [18]. IL-6 expression seems to participate in the process of angiogenesis and vascular remodeling in placenta through the
induction of VEGF expression [19, 20]. IL-6 seems also
to be involved in the induction and progress of the labor,
however the mechanism regulating this process is not
defined [21]. Steinborn et al. documented the growth of
the number of fetal monocytes and IL-6 concentration in
umbilical blood during the spontaneous beginning of the
labor. It was not only observed in decidua and in amniotic fluids but also in the umbilical blood. The fetal
monocytes and macrophages seem to be the source of
IL-6 apart from amniotic membrane and decidua [22].
Interleukin-6 induces a concentration-related increase in
prostaglandin production by amnion and decidual cells,
upregulates production of PGE2 and PGF2α, the receptor of PDGFR in human amnion and decidual cells in
vitro [23]. Moreover, IL-6 stimulates also the uterine
contractility by stimulating the expression of oxytocin receptor [24]. As a key regulator of the immune response,
IL-6 controls the progression of inflammation and differentiation of T cells. The alterations in IL-6 ligand, its
receptors and the inhibitory sgp130 seem to be strongly
related with various complications of pregnancy, including unexplained infertility, preeclampsia and preterm
birth [21].
Cancer microenvironment
In cancer, similarly to immune mediated diseases
the significance of IL-6 seems to be very complex. Ovarian cancer represents the second most common women
reproductive tract cancer, following uterine cancer,
causes more deaths per year than any other female reproductive tract cancer. This cancer is also characterized by the recurrent course and developing of the
resistance to the chemotherapy. The recurrent course
of the disease is related with the biological adaptation of
cancer cells and results from the ability of cancer cells to
survive by local dissemination and the implantation to
the peritoneal serosa. This results from the genetic instability of the cells and development of the resistance
to chemotherapy and apoptosis. The auto/paracrine system of growth factors secretion might also play an important role in this process. Ovarian cancer develops
from the cells that physiologically are responsible for the
secretion of cytokines and growth factors. This secretion
is controlled by the hypothalamo-hypophyseal axis. Human ovarian surface epithelial cells as well as granular
cells secrete IL-6 [25]. Also, IL-6 was reported to play an
important role in renal cancer expansion. As it was
mentioned above, the primary role of IL-6 is related with
hematopoiesis, maturation of lymphocytes, the secretion
of acute phase proteins as well as immunity (by factors
determining antigens presentation and differentiation
of B lymphocytes). Physiologically IL-6 regulates the
growth of B lymphocytes and is the main factor inducing
the production of acute phase proteins by hepatocytes
(like C-reactive protein-CRP). CRP augments the immune response by activating the alternative complement
activation, potentiates the phagocytosis, prevents autoimmunization. IL-1 is strongly involved in the processes
of activation of T lymphocytes. IL-6 and IL-1 are important factors in the maturation and differentiation of
hematopoietic cells, IL-6 together with GMCSF and IL-3
induces the pluripotential stem cell differentiation into
The complex role of Il-6 in physiology and pathology
multipotential myeloid cell, inducing further differentiation into megacariocyte line [26]. Both, IL-6 and IL-1,
might induce the proliferation of epithelial ovarian cells.
IL-6 is produced by epithelial and granular ovarian cells.
Physiologically IL-6 regulates the growth of B lymphocytes, in multiple myeloma it is secreted by cancer cells
which express the receptor of this cytokine and use IL-6
as a growth factor in the mode of autocrine stimulation
of growth [27]. As mentioned above, IL-6 induces the
production and secretion of acute phase proteins
including CRP (C-reactive protein) by hepatocytes [28],
the activity of CRP has a general range, it can be measured in the blood serum and is increased in patients
with infection or after an injury [29]. In immune system,
IL-6 activity is closely related with the maturation of B
lymphocytes and stimulation of the production of
antibodies. In ovarian cancer, IL-6 was observed to be
secreted more commonly by the papillary carcinoma
[30]. The ability of cancer cells to produce IL-6 was
determined by the tendency to organize into defined
morphological forms [31] and the cancer grade [32, 33].
Serous and mucinous ovarian cancer cells produced IL-6,
while endometrioid cancer cells had no such ability.
Ovarian cancer cells retain the ability to produce and
secrete IL-6 and this is related with tumor morphology
and grading. Undifferentiated ovarian cancer cells do not
produce IL-6 [32, 33]. The level of IL-6 in ovarian cancer
microenvironment results from the physiological secretion of this cytokine by the ovary and its level in peritoneal cavity, unspecific increased concentration of IL-6
resulting from the response to the cancer growth and
the injury of the tissues related with cancer spread and
infiltration, IL-6 production by ovarian cancer cells
independent of the mechanisms of control [25]. IL-6
level in ovarian cyst is significantly lower than in ovarian
cancer, it is also higher in peritoneal fluid from patients
with ovarian cancer than in patients with digestive tract
malignant neoplasms [31]. The correlation between IL-6
and CRP is very strong and the level of CRP reflects IL-6
activity. CRP fluid concentration was considered as a potential marker for the course of ovarian cancer. For
example, in renal cancer the level of CRP is the marker
worsening the prognosis of the disease [34]. In ovarian
cancer, however, it appeared that CRP was statistically
significantly correlated with the amount of peritoneal
fluid, creating a poor prognostic factor, however the multivariate analysis of the risk revealed that CRP was not
an independent negative prognostic factor [35].
Thus, IL-6 was demonstrated to have a tumor-promoting activity. Recently, it was shown in ovarian cancer
147
that IL-6 enhances tumor cell survival and increases resistance to chemotherapy through JAK/STAT signaling
pathway in tumor cells [36] and IL-6 receptor transsignaling on tumor endothelial cells [37]. Moreover,
Nilsson et al. demonstrated that IL-6 play an important
pro-angiogenic role in ovarian cancer [38]. IL-6 was also
shown to inhibit the generation of CD4+ Treg cells by
suppressing TGF-β-induced Foxp3 expression [39, 40].
It was also documented that IL-6 together with TGF-β,
induced Th17 cell differentiation from naïve T cell, this
process was negatively regulated by IFN-γ and IL-27 or
IL-2 [2, 41]. Arylhydrocarbon receptor (Ahr) was specifically induced in naïve T cells under Th17 polarizing
conditions (TGF-β, IL-6) and participated in the differentiation of Th17 cells [2, 41, 42]. It was also observed that
Th17 positive regulation was controlled by STAT3, while
negative regulation was controlled by STAT1 and
STAT5. Moreover, Ahr was demonstrated to negatively
regulate lipopolysaccharide (LPS)-induced inflammatory
responses in macrophages [41, 42], it was suggested
that Ahr which is under IL-6 control, might regulate the
immune responses and inflammation through the regulation of T cells and macrophages [2, 41, 42]. Finally, IL-6
was shown to belong to a malignant cell autocrine cytokine network in ovarian cancer cells [42]. Coward et al.
investigated the use of Siltuximab in human ovarian cancer. Siltuximab is a monoclonal, chimeric anti-IL-6 antibody. Siltuximab neutralized the negative Il-6 activity in
ovarian cancer (production of inflammatory cytokines,
angiogenesis of the tumor, infiltration of macrophages),
however the response rate was 5.6% [43]. Siltuximab has
been already investigated in Castelman’s disease, where
the response rate reached 52%, while in prostate cancer
it was only 3.2% [43].
Summarization
In conclusion, IL-6 participates in the broad spectrum of biological processes such as immune responses,
oncogenesis, in pregnancy it enables the maintenance of
the balance between immunoregulatory activity of the
placenta, maternal immune system and fetal immune
system, finally co-creating the phenomenon of the immune tolerance during pregnancy. The deregulation of
IL-6 production and expression of IL-6 membrane and
soluble receptors results in various pathologies such as
immune mediated diseases, chronic inflammations, recurrent miscarriages, preeclampsia, preterm birth, malignant neoplasms including multiple myeloma, ovarian
cancer and others. The biological activity of IL-6 is determined by the tumor microenvironment. The future un-
M. Dutsch-Wicherek,, W. Kaźmierczak, U. Gręźlikowska
148
derstanding of the complex regulation of the biological
activity of this cytokine might provide the new therapeutic strategies in various inflammatory and neoplasmatic
diseases.
Acknowledgments
We would like to thank Dr Zbigniew Pawlowicz for generating
the conditions advantageous for our research. We wish also to
thank prof. Andrzej Lange, for his advice, helpful discussions,
and friendly words of support.
The authors declare no conflict of interest
References
[1] Akira S., Taga T., Kishimoto T. (1993) Interleukin-6 in
biology and medicine. Adv. Immunol. 54: 1-78.
[2] Kishimoto T. (2010) IL-6: from its discovery to clinical applications. International Immunology 22: 347-352.
[3] Nishimoto N. (2007) Interleukin-6 and Castelman’s disease. [In:] (Eds) Caligiuri M.A., Lotze M.T. Cytokines in
the genesis and treatment of cancer. Cancer Drug Discovery and Development; Humana Press, Totowa: 155-163.
[4] Hirano T., Yasukawa K., Harada H. et al. (1986) Complementary DNA for a novel human interleukin (BSF-2) that
induces B lymphocytes to produce immunoglobulin. Na-
ture 324: 73-76.
[5] Hirano T. (1998) Interleukin 6 and its receptor: ten years
later. Int. Rev. Immunol. 16: 249-284.
[6] Diehl S., Rincon M. (2002) The two faces of IL-6 on
Th1/Th2 differentiation. Mol. Immunol. 39: 531-536.
[7] Sikorski K., Czerwoniec A., Bujnicki J.M. et al. (2011)
STAT1 as a novel therapeutical target in pro-atherogenic
signal integration of IFN-γ TLR4 and IL-6 in vascular
disease. Cytokine Growth Factor Rev. 22: 211-219.
[8] Jones S.A., Horiuchi S., Topley N. et al. (2001) The soluble interleukin 6 receptor: mechanisms of production
and implications in disease. FASEB J. 15: 43-58.
[9] Jones S.A. (2005) Directing transition from innate to acquired immunity:defining a role for IL-6. J. Immunol. 175:
3463-3468.
[10] Narazaki M., Yasukawa K., Saito T. et al. (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.
[11] Jostock T., Mullberg J., Ozbek S. et al. (2001) Soluble
gp130 is the natural inhibitor of soluble IL-6 receptor
transsignaling responses. Eur. J. Biochem. 268: 160-167.
[12] Yokota S., Imagawa T., Mori M. et al. (2012) Safety and
efficacy of tocilizumab, an anti-IL-6-receptor monoclonal
antibody, in patients with polyarticular-course juvenile
idiopathic arthritis. Mod. Rheumatol. 22: 109-115.
[13] Naugler W.E., Karin M. (2008) The wolf in sheep's clothing: the role of interleukin-6 in immunity, inflammation
and cancer. Trends Mol. Med. 14: 109-119.
[14] Tabibzadeh S., Kong Q.F., Babaknia A. et al. (1995)
Progressive rise in the expression of interleukin-6 in
human endometrium during menstrual cycle is initiated during the implantation window. Hum. Reprod. 10:
2793-2799.
[15] Desai N., Scarrow M., Lawson J. et al. (1999) Evaluation
of the effect of interleukin-6 and human extracellullar
matrix on embryonic development. Hum. Reprod. 14:
1588-1592.
[16] Stephanou A., Handwerger S. et al. (1994) Interleukin-6
stimulates placental lactogen expression by human trophoblast cells. Endocrinology 135: 719-723.
[17] Champion H., Innes B.A., Robson S.C. et al. (2012) Effects of interleukin-6 on extravillous trophoblast invasion
in early human pregnancy. Mol. Hum. Reprod. 18: 391-
400.
[18] De M., Sanford T.H., Wood G.W. (1992) Deletion of Inter-
leukin-1, Interleukin-6, and tumor necrosis factor alpha in
the uterus during the second half of pregnancy in the
mouse. Endocrinology 131: 14-20.
[19] Motro B., Itin A., Sachs L., Keshet E. Pattern of interleukin 6 gene expression in vivo suggests a role for this cytokine in angiogenesis. Proc. Natl. Acad. Sci. USA 87:
3092-2096.
[20] Cohen T., Nahari D., Cerem L.W. et al. (1996) Interleukin
6 induces the expression of vascular endothelial growth
factor. J. Biol. Chem. 271: 736-741.
[21] Prins J.R., Gomez-Lopez N., Robertson S. (2012) Interleukin-6 in pregnancy and gestational disorders. J. Re-
prod. Immunol. 95: 1-14.
[22] Steinborn A., Sohn C., Sayehli C. et al. (1999) Sponta-
neous labour at term is associated with fetal monocyte
activation. Clin. Exp. Immunol. 117: 147-152.
[23] Mitchell M.D., Dudley D.J., Edwin S.S. et al. (1991) Interleukin-6 stimulates prostaglandin production by human
amnion and decidual cells. Eur. J. Pharm.. 192: 189-191.
[24] Fang X., Wong S., Mitchell B.F. (2000) Effects of LPS and
IL-6 on oxytocin receptor in non-pregnant and pregnant
rat uterus. Am. J. Reprod. Immunol. 44: 65-72.
[25] Kryczek I., Gryboś M., Lange A. (1999) Biological and
clinical impact of IL-6 production by ovarian carcinoma
cells. Współczesna Onkologia 3: 195-198.
[26] Wognum A., de-Jong M., Wagemaker G. (1996) Differential expression of receptors for hemopoietic growth factors on subsets of CD34+ hemopoietic cells. Leuk-Lym-
phoma 24: 11-25.
[27] Donovan K., Lacy M., Kline M. et al. (1998) Contrast in
cytokine expression between patients with monoclonal
gammapathy of undetermined significance or multiple
myeloma. Leukemia 12: 593-600.
[28] May L., Patel K., Garcia D. et al. (1994) Sustained high
levels of circulating chaperoned interleukin-6 after active
specific cancer immunotherapy. Blood 84: 1887-1895.
[29] Planz B., Wolff J., Gutersohn A. et al. (1997) C-reactive
protein as a marker of tissue damage in patients undergoing ESWL with or without retrograde stone manipulation. Urologia Internationalis 59: 174-176.
[30] Kutteh C. (1992) Quantitation of tumor necrosis factor
alpha, interleukin-1-beta, and interleukin-6 in the effusion
of ovarian epithelial neoplasms. Am. J. Obstet. Gynecol.
167: 1864-1869.
[31] Kryczek I., Gryboś M., Karabon L. et al. (2000) IL-6 pro-
duction in ovarian carcinoma is associated with histiotype
and biological characteristics of the tumour and influences local immunity. Br. J. Cancer. 82: 621-628.
The complex role of Il-6 in physiology and pathology
[32] Rabinovich H., Suminami Y., Reichert T. et al. (1996) Ex-
149
pression of cytokine genes or proteins and signaling molecules in lymphocytes associated with human ovarian
carcinoma. Nt. J. Cancer 68: 276-184.
[40] Bettelli E., Korn T., Kuchroo V.K. (2007) Th17: the third
member of the effector T cell trilogy. Curr. Opin. Immunol. 19: 652-657.
[41] Kimura A., Naka T., Nohara K. et al. (2008) Aryl hydro-
Alterations in expression and function of signal-transducing proteins in tumor-associated T and natural killer cells
in patients with ovarian carcinoma. Clin. Cancer Res. 2:
Sci. USA 105: 9721.
[42] Kimura A., Naka T., Nakahama T. et al. (2009) Aryl hydro-
[33] Lai P., Rabinovich H., Crowley-Nowick P. et al. (1996)
161-173.
[34] Masuda H., Kurita Y., Fukuta K. et al. (1998) Significant
prognostic factors for 5-year survival after curative resection of renal cell carcinoma. Int. J. Urol. Sep. 5: 418-422.
[35] Kodama J., Miyagi Y., Seki N. et al. (1999) Serum C-reactive protein as a prognostic factor in patients with epithelial ovarian cancer. Eur. J. Obstet. Gynecol. Reprod.
Biol. 82:107-110.
[36] Duan Z., Foster R., Bell D.A., et al. (2006) Signal trans-
ducers and activators of transcription 3 pathway activation in drug-resistant ovarian cancer. Clin. Cancer Res.
12: 5055-5063.
[37] Lo C.W., Chen M.W., Hsiao M., et al. (2011) IL-6 trans-
signaling in formation and progression of malignant ascites in ovarian cancer. Cancer Res. 71: 424-434.
[38] Nilsson M.B., Langley R.R., Fidler I.J. (2005) Interleukin-6, secreted by human ovarian carcinoma cells, is a potent proangiogenic cytokine. Cancer Res. 65: 10794-
10800.
[39] Bettelli E., Carrier Y., Gao W. et al. (2006) Reciprocal
developmental pathways for the generation of pathogenic
effector TH17 and regulatory T cells. Nature 441: 235-
238.
carbon receptor regulates Stat1 activation and participates in the development of Th17 cells. Proc. Natl. Acad.
carbon receptor in combination with Stat1 regulates LPSinduced inflammatory responses. J. Exp. Med. 206: 2027-
2035.
[43] Kulbe H., Thompson R., Wilson J.L. et al. (2007) The in-
flammatory cytokine tumor necrosis factor-alpha generates an autocrine tumor-promoting network in epithelial
ovarian cancer cells. Cancer Res. 67: 585-592.
[44] Coward J., Kulbe H., Chakravarty P. et al. (2011) Interleukin-6 as a therapeutic target in human ovarian cancer.
Clin. Cancer Res.17: 6083-6096.
J
Magdalena Dutsch-Wicherek
Laryngology Outpatients Unit
Lukaszczyk Oncological Center in Bydgoszcz
85-796 Bydgoszcz, Romanowskiej 2, Poland
e-mail: [email protected]