International Journal of Rheumatic Diseases 2013; 16: 243253

REVIEW ARTICLE

Th17 Cells in Immunopathogenesis and treatment of

rheumatoid arthritis
Gholamreza AZIZI,1 Farhad JADIDI-NIARAGH2 and Abbas MIRSHAFIEY2
1
Imam Hassan Mojtaba Hospital, Alborz University of Medical Sciences, Karaj, Iran and 2Department of Immunology, School of
Public Health, Tehran University of Medical Sciences, Tehran, Iran

Abstract
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by the sequestration of various leuko-
cyte subpopulations within both the developing pannus and synovial space. The chronic nature of this disease
results in inflammation of multiple joints, with subsequent destruction of the joint cartilage and erosion of bone.
Identification of T helper (Th)17 cells led to breaking the dichotomy of the Th1/Th2 axis in immunopathogenesis
of autoimmune diseases such as RA, and its experimental model, collagen-induced arthritis (CIA). Th17 cells
produce cytokines, including interleukin (IL)-17, IL-6, IL-21, IL-22 and tumor necrosis factor (TNF)-a, with pro-
inflammatory effects, which appear to have a role in immunopathogenesis of RA. Regarding the wide ranging pro-
duction of pro-inflammatory cytokines and chemokines by Th17 cells, it is expected that Th17 cell could be a
potent pathogenic factor in disease immunopathophysiology. Thus the identification of effector mechanisms used
by Th17 cells in induction of disease lesions may open new prospects for designing a new therapeutic strategy for
treatment of RA.
Key words: IL-17, immunopathogenesis, RA, rheumatoid arthritis, Th17.

INTRODUCTION TH17 CELLS

+
The newly identified CD4 T helper (Th) cell subtype,
Th17 cells, are characterized by production of a
distinct profile of effector cytokines, including inter-
leukin (IL)-17A, IL-17F, IL-6, IL-9, IL-21, IL-22, IL-26
and tumor necrosis factor (TNF)-a. They have proba-
bly evolved to promote host clearance of a range of
pathogens distinct from those targeted by Th1 and
Th2.1,2 Th17 produces cytokine profiles, including
IL-17, IL-6, IL-21, IL-22 and TNF-a, which have pro-
inflammatory functions, suggesting an important
factor in immunopathogenesis of rheumatoid arthritis
(RA), because the main feature of RA pathophysiology
is the inflammatory reaction.35
Correspondence: Professor Abbas Mirshafiey, Department of
Immunology, School of Public Health, Tehran University of
Medical Sciences, Tehran-14155, Box 6446, Iran.
Email: mirshafiey@tums.ac.ir
The first sign of Th17 cells identification relates to the
role of these cells in host immune response to Borrelia
burgdorferi which induced the production of IL-17 by
Th17.6 The IL-17 cytokine family is a recently identified
group of cytokines, which includes six members:
IL-17A, B, C, D, E (IL-25), and F. IL-17A, the original
member of this family was identified in 1995. Different
cell types, including Th17, cdT cells, natural killer (NK)
cells and neutrophils, produce IL-17A and IL-17F.7,8
The molecular mechanisms of Th17 cell differentia-
tion were intensively studied approximately a decade
ago and a number of signaling cascades and transcrip-
tion factors have been shown to be involved.9 Th17
differentiation is promoted by lineage-specific transcrip-
tion factors, including retinoic acid-related orphan
receptor (ROR)ct and RORa, and is controlled by the
coordinated function of a complex of positive and neg-
ative regulators. In mice, the differentiation of Th17
cells is initiated by transforming growth factor (TGF)-b,

2013 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
G. Azizi et al.
IL-6, and IL-21, which activate signal transducer and
activator of transcription (STAT)3 and induce the
expression of transcription factor RORct. In humans,
IL-1, IL-6 and IL-23 promote human Th17 differentia-
tion, but to date, the role of TGF-b in Th17 cell genera-
tion remains unclear.1012
It is demonstrated that during initial Th17 develop-
ment, IL-6 induces IL-21 in early activated CD4+ T cells,
thus acting as a positive amplification loop to enforce
Th17 differentiation.13,14 Although it is reported that
the presence of IL-6 is essential for Th17 cell differentia-
tion, it has been shown this lineage can be generated by
IL-21 in IL-6 deficient mice.14 On the other hand, Shaw
et al.15 in 2012 demonstrate that IL-1b, but not IL-6, is
required for the development of RORct-expressing
Th17 cells. Also in opposition to IL-6 signaling (via
STAT3 and STAT1), IFN-c signaling can reduce develop-
ment of pathogenic Th17 effector cells.16
As previously mentioned, a number of trials report
that TGF-b as a direct effector is involved in Th17 cell
development in mice. On the other hand, it is shown
that TGF-b suppresses development of Th1 and Th2
cells by inhibition of their lineage-specific transcription
factors, including T-bet and GATA-3, suggesting that
this cytokine acts as an indirect effector in Th17 cell
differentiation.17,18 However, Schumann et al.19 in
2012 indicated that TGF-b signaling in T cells is
dispensable or even an inhibitor for generation of Th17
cells in mice.
IL-21, a member of the IL-2 family can also control
the generation of Th17 cells, although it is reported that
the absence of IL-21 or IL-21R has no significant effect
on Th17 differentiation.20 IL-21 action is mediated by
IL-6 in a STAT3 dependent manner and STAT3 may
directly regulate the IL-21 gene.12,21 IL-21 binds to a
receptor complex composed of a unique IL-21Ra chain
and the shared common c chain, which activates the
STAT1/STAT3 pathway.21
IL-23, which activates STAT3, is another effector cyto-
kine involved in the fate of Th17 in the first 5 days after
the initiation of the Th17 developmental program. It
seems that IL-23 is not involved in the early stage of
Th17 differentiation, because naive T cells express
IL-23R at a low level.22 Possibly, impaired differentia-
tion of Th17 cells in the absence of heterodimeric
IL-23R complex is due to impaired expression of IL-
17Ra.23,24 Also it is shown that although IL-23 is not
involved in the initiation of the Th17 development pro-
gram, it is required for the full terminal differentiation
of Th17 and ultimately its activity.25,26 Recently, it was
reported that IL-23 promotes Th17 differentiation by
244
inhibiting T-bet and FoxP3 and is required for elevation
of IL-22 but not IL-21.27 IL-22 is produced by Th17 and
it was recently discovered that Th22 cells are able to
produce this cytokine in the absence of IL-17. However,
it remains unclear whether IL-22 and Th22 cells con-
tribute to T cell-mediated synovial inflammation.28
In addition to RORct and RORa, other transcription
factors are also identified which effect differentiation
and development of Th17 cells, including RORc,29
STAT3,30 aryl hydrocarbon receptor (AhR) or dioxin
receptor,31,32 interferon regulatory factor-4 (IRF-4)33
and a recently identified transcription factor, BATf, a
basic leucine zipper transcription factor.26
It is revealed that Th1 hallmark cytokines, including
IFNc and IL-12, can promote Th1 differentiation and
inhibit Th17 development, since IFNc can prevent
IL-23-triggered expansion of Th17 cells.16 Moreover,
IFNc increases T-bet expression and T-bet overexpres-
sion leads to robust reduction of IL-17 generation.
Surprisingly, T-bet can promote Th17 development,
because T-bet can bind to the IL-23R promoter and pro-
mote its expression.3437 STAT1 and STAT4 mediate
IFNc and IL-12 signaling, and it seems that these two
transcription factors are also negative regulators of
Th17 development, because IL-17 production in
STAT1-deficient T cells is increased.16 Conversely, Th17
cell development in STAT1-, STAT4- and T-bet-deficient
mice is unaffected, suggesting that these transcription
factors have no significant effects in Th17 develop-
ment.38,39 IL-27, a member of the IL-12 family of cyto-
kines is also the negative regulator of Th17 cells. Like
the IFNc, IL-27 signaling is through engagement of
STAT1 transcription factor. The producer cells of this
cytokine are macrophages and dendritic cells and their
signaling are mediated through a receptor composed of
IL-27R (WSX1 or TCCR) and the gp130 chain.4043 In
addition, IFNb inhibits Th17 development through
induction of IL-27.44
Like Th1 cells, Th2 cytokines and their transcription
factors which promote Th2 development, inhibit Th17
differentiation and expansion, so that IL-4 can inhibit
both Th1 and Th17 differentiation and expansion.16
GATA-3, c-Maf, and STAT6 are the Th2 lineage-specific
transcription factors which promote Th2 differentiation
and inhibit Th17 development.16,38,45 Moreover, IL-25
(a member of IL-17 cytokine family) can inhibit Th17
development and enhance Th2 differentiation via IL-13
induction. IL-13 inhibits Th17 cell development in
dendritic cells via down-regulation of Th17 stimulatory
cytokines (IL-1, IL-6 and IL-23).46 Despite the inhibi-
tory effect of GATA-3 on Th17 development, it seems
International Journal of Rheumatic Diseases 2013; 16: 243253

that GATA3 probably promotes Th17 development
through inhibition of IL-2, STAT1 and suppressors of
cytokine signaling 3 (SOCS3).47
IL-2 is a T cell growth factor that is critical for Treg
development. It effectively inhibits Th17 cell develop-
ment. Two pivotal transcription factors that mediate
IL-2 signaling are STAT5a/b. Therefore IL-2 or STAT5
deficiency is associated with inhibitory effects of Tregs
and expansion of Th17 cells.4851
The transcription factor Ets-1, which is a positive reg-
ulator of Th1 development, is another negative regula-
tor for Th17 development. Ets-1 deficiency leads to
increased Th17 differentiation and promotion of IL-22
and IL-23R messenger RNA (mRNA) levels in response
to IL-6 and TGF-b1. It seems that the inhibitory effect of
Ets-1 on Th17 cells is through enhancing IL-2 produc-
tion.52 In a recent report, it has been shown that micro-
RNA mir-326 can bind to and prevent translocation of
Ets-1 mRNA. Thus, microRNAs can promote Th17
development through inhibition of the Th17 inhibitor,
Ets-1.1158
It should be noted that the transcriptional repressor
protein BCL-6 regulates T cell differentiation by repress-
ing Th2 cells and enhancing follicular Th cells. It is
proposed that BCL-6 enhances Th17 differentiation
through suppression of Th2 differentiation.54
TH17 CELLS AND RA
Th17 cells are the dominant pathogenic cellular compo-
nent in autoimmune inflammatory diseases, including
RA.55 Although the importance of Th17 cells in animal
models of arthritis is unquestionable, there are only
limited data on the role of Th17 cells and related cyto-
kines in human arthritic diseases. In addition, the char-
acteristics of human Th17 cells have not been fully
defined, and there seems to be substantial differences
between human and mouse Th17 cells.56
Functionally, Th17 cells contribute to host defense by
having a role in protection against extracellular bacteria.
However, their activities are also pivotal in the develop-
ment of autoimmune diseases under pathologic condi-
tions.57 The identification of Th17 and IL-17 as a
powerful pro-inflammatory cytokine, have focused
attention on the role of Th17 cells in RA and other
immune-mediated diseases, such as psoriasis, Crohns
disease and multiple sclerosis.5,58
The hyperfunction of Th17 cells is associated with
autoimmune diseases, due to the hypersecretion of the
pro-inflammatory cytokine IL-17.59 Studies in rodents,
mammalian cell culture systems, as well as clinical
International Journal of Rheumatic Diseases 2013; 16: 243253
Th17 Cells and RA
settings, support a specific role for IL-17 in promoting
RA.60 Additional supporting evidence came from IL-17
knock-out animals that failed to develop collagen-
induced arthritis (CIA).61 Research on pathogenesis of
the autoimmune diseases and development of new
drugs is due to expanded studies on experimental
animal models which mimic human diseases. CIA in
genetically susceptible strains of mice, rats, rabbits or
rhesus monkeys has been used as an experimental
model of RA, as it shares many histological and
immunological features.62
In addition to IL-17 and other previously mentioned
cytokines, Th17 cells are characterized by expression of
IL-6 and TNF.63 IL-17 plays an important role in the
additive/synergistic effects induced together with TNF-a
and IL-1, two key cytokines in destructive arthritis.4,60,64
The synergy between monocyte-derived IL-1b and TNF
and T cell-derived IL-17 also causes the up-regulation of
CCL20 in RA synoviocytes, a protein involved in the
chemotaxis of T cells and immature dendritic cells.65
Consequently, RA synovium is characterized by elevated
levels of IL-17, IL-23, IL-6, TNF and IL-1b, along with
nitric oxide (NO) and prostaglandin E2 (PGE2).66
On the other hand, B cell-activating factor (BAFF) as
a TNF superfamily member, also plays an important
role in humoral immunity and in autoimmune
diseases, including RA. Local BAFF gene targeting could
inhibit pro-inflammatory cytokine expression,
suppressed generation of plasma cells and Th17 cells,
and markedly ameliorated joint pathology.67 BAFF
gene-silenced DCs show defective IL-6 production and
display severely impaired capacity, inducing Th17-cell
generation in vitro. These results are consistent with
previous findings that APC-produced IL-6 is critically
involved in driving Th17 cells to induce T cell reactivity
in SKG mice, so that a previously unrecognized role for
BAFF in promoting the expansion of Th17 cells was
shown and IL-17 was demonstrated as a crucial effector
cytokine for BAFF-mediated pro-inflammatory effects
during CIA development.67,68
Although the increased levels of IL-17A, IL-6, TGF-b,
and IFN-c concentrations in sera and synovial fluid of
reactive arthritis (ReA) and undifferentiated spond-
yloarthropathy (uSpA) compared to RA suggests that
Th1 and Th17 cells could be the major cells in RA, it
remains unclear whether Th1 and/or Th17 cells are
involved in driving disease chronicity and destruc-
tion.69,70
The differentiation of Th17 cells from naive T cells
appears to involve signals in connection with TGF-b, IL-
6, IL-21, IL-1b and IL-23. IL-23 is one of the essential
245
G. Azizi et al.
factors required for the survival and/or expansion of
Th17 cells to promote inflammatory responses.71 Th17
cells stimulated by IL-23 promote osteoclastogenesis
through production of IL-17, which induces receptor
activators of nuclear factor (NF)-j B ligand on mesen-
chymal cells. The IL-23/IL-17 axis includes Th17 cells
and plays a key role in the development of autoim-
mune arthritis by stimulating receptor activators of
NF-jB ligand (RANKL) expression.72 It is possible that
homoeostatic mechanisms can effectively control IL-23
production, and reports (somewhat paradoxically)
have described that TNF-a negatively regulates IL-23
(and IL-12) in mouse APCs during an inflammatory
response.73 Moreover, it should be noted that adding
anti-TNF-a to RA synovial cell cultures did not increase
IL-23 cell-associated levels, whereas a reduction (non-
significant) in p19 mRNA levels was observed.10,22,73
In mice, systemic IL-23 exposure induced chronic
arthritis, severe bone loss, and expanded myeloid line-
age osteoclast precursors in the bone marrow, which
resulted in increased osteoclast differentiation and
systemic bone loss as observed in RA and other types
of autoimmune arthritis.60,74 Moreover, in conflict
with its effects, IL-23 also dose-dependently inhibited
osteoclastogenesis in a CD4+ T lymphocyte-dependent
manner. Like IL-12,
IL-23 acts synergistically with IL-18 to block osteoclas-
togenesis but, unlike IL-12, IL-23 action depends on T
cell granulocyte-macrophage colony-stimulating factor
(GM-CSF) production. Thus, IL-23 is able to inhibit
osteoclast formation indirectly via T cells.75
In RA, expression of IL-22 was found to be up-regu-
lated in synovium with ability to induce synovial fibro-
blast proliferation and chemokine production.76,77 The
high levels of IL-22 were expressed both in the lining
and the sublining layers of RA synovial tissues.77,78 The
paucity of IL-22-producing CD4 T cells in synovial fluid
(SF) lends support to the notion that the primary
source of IL-22 in the joint is synovial fibroblasts and/
or macrophages but not T cells, based on the report of
Ikeuchi et al.76,77
In RA, IL-21 can regulate the function of T, B, NK and
DC cells, and pro-inflammatory cytokine secretion in
immune responses. IL-21 expression shows a correla-
tion with the presence of Th17 cells in the synovium, SF
and peripheral blood in RA patients. It has been
reported that human CCR6+ CD4+ T cells can produce
high levels of both IL-21 and IL-17. Similar to mouse T
cells, IL-21 auto-regulates its own production in human
CD4+ T cells.79 In addition, IL-21 forms a positive-feed-
back autocrine loop involving homeostatically activated
246
CD4+ cells, which is essential in the progression of auto-
immune arthritis by mechanisms dependent on follicu-
lar Th cell development, autoreactive B cell maturation,
and RANKL induction, but is independent from Th17
cell function.80
Here, we have focused on the role of Th17 cells in
inducing and perpetuating chronic inflammation, carti-
lage damage and bone erosion which are hallmark
phases of joint destruction (Fig. 1). The aim of current
and emerging therapies is to seek a way for disrupting
the inflammatory Th17 network and shifting the
immune system back toward homeostasis.81
CHRONIC INFLAMMATION
In this section, the potential dynamic of Th17 cell pop-
ulations and their interplay with other inflammatory
cells in inducing tissue inflammation in organ-specific
autoimmunity are reviewed.82
Various animal models have demonstrated key roles
of IL-17A (henceforth called IL-17) and Th17 cells in
immunopathology and joint damage of arthritis.83
Moreover, two other members of the IL-17 cytokine
family, IL-17B and IL-17C, have also been implicated in
chronic inflammation in an experimental model of
arthritis, in which CD4+ T cells transduced with IL-17B
or IL-17C exacerbated murine CIA to the same degree
as IL-17, and both cytokines could stimulate the expres-
sion of pro-inflammatory IL-1b, IL-6, TNF and
IL-23.81,84
It is thus possible that the inflammatory environment
of the rheumatoid synovium can drive Th17 cells to
produce IL-17 in a cytokine-dependent manner. More-
over, the concept that CD4+ T cells may not be the only
source of IL-17 in the joint is being increasingly recog-
nized. For example, mast cells have recently been iden-
tified as a source of IL-17 in RA synovium and are
potent producers of IL-17 upon stimulation with TNF-
a, immune complexes and LPS.76,85 Basically, the high
levels of mast cells are observed in avascular, fibrotic
regions of RA synovial tissue, without any correlation
with lymphocytic infiltration.86
Several studies have recently proposed neutrophils
and Th17 cells as key players in the onset and perpetua-
tion of this disease. The main goal of recent studies was
to determine whether cytokines driving neutrophil and
Th17 activation are dysregulated in very early RA
patients.87 In addition to inducing a highly inflamma-
tory cytokine milieu, IL-17 drives osteoclastogenesis,
neoangiogenesis and the subsequent recruitment of
innate immune cells that amplify more inflammation
International Journal of Rheumatic Diseases 2013; 16: 243253

Figure 1 The role of the Th17 cell in
rheumatoid arthritis pathogenesis. In
the inflamed joints Th17 produces
inflammatory cytokines to activate oste-
oclasts and macrophages and also
recruits leukocytes. The infiltrated leuko-
cytes producing cytokines, chemokine
and tissue destructive enzymes lead to
chronic inflammation, cartilage damage
and bone erosion. IL, interleukin; Mo,
monocyte; Neu, neutrophils; MMP,
matrix metalloproteinase; NO, nitric
oxide synthase; ROS, reactive oxygen
species.
in the RA joint.81,88 IL-17 as a potent chemoattractant
for pre-committed CD4+ T cells and neutrophils may
promote the migration of B cells to lymphoid follicles
in the chronic phase of synovial inflammation.89
It has been identified that Th17 cells are within SF and
synovial tissue, and demonstrated that RA synovial
fibroblasts treated with IL-17 and TNF-a can promote
the survival and functional lifespan of neutrophils, asso-
ciated with increased number of neutrophils observed
in the rheumatoid synovium.90 As noticed above, IL-17
promotes recruitment of both neutrophils and mono-
cytes by means of inducing various chemokines. Also
preferential recruitment of CCR6-expressing Th17 cells
to inflamed joints via CCL20 in RA and its animal
model has been shown.65,91
Moreover IL-17 exerts an anti-apoptotic effect, medi-
ated by IL-17RA and IL-17RC, associated with increased
synoviolin expression. These data suggest that IL-17
contributes to RA chronicity through both synovial
inflammation and hyperplasia. The anti-apoptotic role
for IL-17 is supported by data in IL-17R knockout mice
correlated with markedly reduced synovial hypercellu-
larity.92,93
International Journal of Rheumatic Diseases 2013; 16: 243253
Th17 Cells and RA
On the other hand, oxygen metabolism has an
important role in the pathogenesis of RA. Reactive
oxygen species (ROS) are produced in many normal
and abnormal processes in patients with atheroma,
asthma, joint diseases and cancer.94 It has been sug-
gested that the level of ROS in patients with RA is
higher than in healthy subjects.95
It has been demonstrated that IL-17 and TNF-a
promote vascular endothelial growth factor (VEGF)-A
production by RA synovial fibroblasts. This role for IL-
17 in angiogenesis is supported by recent findings that
local overexpression of IL-17 in C57BL/6 mice leads to
arthritis, with increased vascularity along with angio-
genesis.83,96 IL-17 can also up-regulate the constitutive
release of other angiogenic factors from synovial fibro-
blasts, including keratinocyte growth factor (KGF),
hepatocyte growth factor (HGF) and heparin-binding
epidermal growth factor (HB-EGF), all of which are
involved in the proliferation of endothelial cells.81,97
Recently, TNF-positive Th17 cells have been discussed
as potential dangerous cells in driving persistent arthri-
tis in patient with early RA.78 TNF and IL-17 synergisti-
cally have also been proposed to induce the alternative
247
G. Azizi et al.
complement pathway proteins C3 and factor B, both of
which are up-regulated in RA synovial tissue.98 In
conclusion, these data strongly suggest that Th17 is a
key effector cell in driving the acute phase to the
chronic form of RA.89
CARTILAGE DAMAGE
A large number of cytokines are active in the joints of
patients with RA. It is now clear that these cytokines
play a fundamental role in the processes that cause
inflammation, articular destruction and the co-morbidi-
ties associated with RA.99 Two down-stream mecha-
nisms by which the cartilage degradation occurs have
been elucidated: the simultaneous inhibition of proteo-
glycan and collagen synthesis and the catabolism of the
extracellular matrix. It is thought that inflammation in
the adjacent synovial tissue and fluids evokes changes
in the metabolic activity of chondrocytes.88 Further-
more, IL-17 appears to play an active role in the induc-
tion of cartilage matrix breakdown through the
dysregulation of chondrocyte metabolism.78,100
In RA, imbalance occurs in the main cytokine system,
including IL-1, IL-6, IL-13, IL-15, IL-18, IL-22, IL-33
and TNF. The joint destruction seen in RA is caused not
only by this cytokine imbalance, but also by specific
effects of the Wnt system and osteoprotegerin on osteo-
clasts, as well as by dysregulation in matrix production
responsible for cartilage damage.101
Although IL-17F has many biologically overlapping
effects with IL-17A, IL-17F is less potent, for example,
in activating synovial fibroblasts.102 IL-17F has been
shown to have a cartilage destructive potential effect
in vitro.59 In a mouse model, intra-articular injection of
IL-17 into the knee joint resulted in joint inflammation
and damage. Moreover, it is shown that blocking IL-17/
IL-17R signaling could be effective in the control of RA
symptoms and in the prevention of joint destruction.103
Like IL-17A, IL-17F regulates pro-inflammatory gene
expression by a very similar but not identical signaling
pathway involving IL-17RA and IL-17RC.104 Further-
more, data from an experimental model of arthritis
indicated IL-17 receptor signaling is a critical pathway
in turning acute synovitis into a chronic destructive
arthritis.63
BONE EROSION
Th17 cells and IL-17 in particular have been increas-
ingly implicated in bone degradation that occurs in
inflamed joints.105 The bone destruction associated
248
with RA is mainly attributed to the abnormal activation
of osteoclasts, which are terminally differentiated cells
of monocyte/macrophage lineage that resorb bone
matrix. Studies on the immune regulation of osteoclasts
in RA have promoted the new research field of osteo-
immunology, which investigates the skeletal and
immune systems interplay at the molecular level.106 In
addition, Th17 cells have been identified as exclusively
osteoclastogenic, and thereby joint destructive Th17
cells are able to differentiate tissue macrophages from
osteoclasts. Following stimulation by RANKL and
M-CSF, osteoclasts secrete various intermediates and
pro-inflammatory mediators, such as inducible nitric
oxide synthase (iNOS), to promote bone loss.107,108
It should be noted that primary Th17 cells were
potent inducers of IL-6 and IL-8 and the tissue-destruc-
tive enzymes matrix metalloproteinase (MMP)-1 and
MMP-3 when co-cultured with RA synovial fibroblasts
(RASF), whereas primary Th1 or naive T cells did not.70
It is revealed that IL-17 can affect a wide range of cells,
such as endothelial cells, epithelial cells, fibroblasts,
myeloid cells and synoviocytes. Moreover, IL-17 can
enhance the secretion of various inflammatory media-
tors, including IL-8, CXCL1, CXCL6, IL-1b, IL-6, TNF-a,
GM-CSF, MIP-2, MCP-1 and G-CSF.3,109,110
The roles of IL-17 and IL-23 on other bone-destruc-
tive conditions are complex and not necessarily patho-
genic. For example, the most common form of bone
loss in humans is actually due to infectious diseases in
the oral cavity that lead to periodontal disease and
destruction of the alveolar bone crest of the jaw.
However, the elevated levels of IL-17 are found in some
instances of human periodontal disease.60,111
CYTOKINES AND TREATMENT
Cytokines involved in the Th17 network, including
IL-6, IL-1b and TNF, have been targeted in therapies for
RA, although to date no clinical trials have directly
tested the efficacy of anti-IL-17 treatment. However, the
synergy between IL-17 and TNF may partially explain
the efficacy of TNF inhibitors in attenuating the symp-
toms of RA.112
In RA, the beneficial effect of anti-TNF
(adalimumab) therapy might involve a decrease in
Th17-related cytokines in responders, whereas rising
levels of circulating Th17-cells and IL-17 were
observed in patients with an inadequate response to
anti-TNF-a therapy.113 Even these increases in periph-
eral Th17 cells after anti-TNF therapy are accompanied
by a decrease in Th17-specific CCR6 expression, which
International Journal of Rheumatic Diseases 2013; 16: 243253

might prevent homing of these potentially pro-inflam-
matory cells to the synovium.114 To date, up to 40%
of RA patients are non-responders to current anti-TNF
therapy, suggesting that other molecules re implicated
in synovial inflammation and/or hyperplasia may
contribute to disease chronicity.93,115 Following the
success of TNF-a blockades as a treatment for RA,
other cytokines and receptors now offer alternative tar-
gets for therapeutic intervention which might be useful
as predictive biomarkers of disease.99
IL-10 is a potent anti-inflammatory cytokine that has
been shown to regulate endogenous pro-inflammatory
cytokine production in RA synovial tissue.116 IL-10
treatment significantly decreases the numbers of IL-17-
producing and RORc-expressing cells among human
CD4+ T cells that has been activated in vitro by Th17-dif-
ferentiating conditions in RA patients. Moreover IL-10
induced Foxp3+ regulatory T cells in the human CD4+ T
cell population.55 It has been demonstrated that IL-4
alone or in combination with IL-10 can protect matrix
formation when used as a pretreatment for cartilage
explants exposed to IL-17.117
New studies indicate that circulating IL-27-producing
CD14+ cells significantly infiltrate into inflamed RA
synovium and have anti-inflammatory effects in several
ways: both directly through the reduction of IL-6
production, and possibly through the induction of Th1
development and the suppression of Th17 develop-
ment, and indirectly by regulation of recruitment of
CCR6+ cells, such as Th17 cells, through the suppres-
sion of CCL20 production.118 In addition as an auto-
regulatory mechanism, IL-17 enhances the expression
of IL-27 in synovial macrophages from RA patients and
CIA mice.119
In conclusion, it seems that Th17 cells play an impor-
tant role in immunopathogenesis of RA, and recognition
of functional mechanisms used by Th17 cells in induc-
tion of disease lesions may open a new outlook for
designing new therapeutic strategies for treatment of RA.
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