Tài liệu Báo cáo khoa học: Molecular aspects of rheumatoid arthritis: chemokines in the joints of patients pdf

MINIREVIEW
Molecular aspects of rheumatoid arthritis: chemokines
in the joints of patients
Takuji Iwamoto
1,2
, Hiroshi Okamoto
1
, Yoshiaki Toyama
2
and Shigeki Momohara
1
1 Institute of Rheumatology, Tokyo Women’s Medical University, Japan
2 Department of Orthopaedic Surgery, School of Medicine, Keio University, Tokyo, Japan
Introduction
Rheumatoid arthritis (RA) is a chronic systemic inflam-
matory disease that occurs in about 1% of the popula-
tion. The inflammatory process is characterized by
infiltration of inflammatory cells into the joints, leading
to the proliferation of fibroblast-like synoviocytes (FLS)
and the destruction of cartilage and bone. In RA syno-
vial tissue, the infiltrating cells consist of macrophages,
T cells, B cells, plasma cells, neutrophils, mast cells,
dendritic cells and natural killer cells [1]. Migration of
leukocytes into the synovium is a regulated multistep
process involving interactions between leukocytes and
endothelial cells and cellular adhesion molecules, as well
as between leukocytes and chemokines and chemokine
receptors [2]. Chemokines are small, chemoattractant
cytokines that play key roles in the accumulation of
inflammatory cells at the site of inflammation. There-
fore, chemokines and chemokine receptors are consid-

ered to be therapeutic targets in several chronic
Keywords
chemokine receptors; chemokines;
monocyte chemoattractant protein-4
(MCP-4) ⁄ CCL13; pulmonary and activation-
regulated chemokine (PARC)/CCL18;
rheumatoid arthritis (RA)
Correspondence
H. Okamoto, Institute of Rheumatology,
Tokyo Women’s Medical University, 10-22
Kawada-cho, Shinjuku, Tokyo 162-0054,
Japan
Fax: +81 3 5269 1726
Tel: +81 3 5269 1725
E-mail:
(Received 14 March 2008, revised 27 May
2008, accepted 27 June 2008)
doi:10.1111/j.1742-4658.2008.06580.x
Rheumatoid arthritis (RA) is a chronic symmetric polyarticular joint dis-
ease that primarily affects the small joints of the hands and feet. The
inflammatory process is characterized by infiltration of inflammatory cells
into the joints, leading to proliferation of synoviocytes and destruction of
cartilage and bone. In RA synovial tissue, the infiltrating cells such as
macrophages, T cells, B cells and dendritic cells play important role in the
pathogenesis of RA. Migration of leukocytes into the synovium is a regu-
lated multi-step process, involving interactions between leukocytes and
endothelial cells, cellular adhesion molecules, as well as chemokines and
chemokine receptors. Chemokines are small, chemoattractant cytokines
which play key roles in the accumulation of inflammatory cells at the site
of inflammation. It is known that synovial tissue and synovial fluid from

RA patients contain increased concentrations of several chemokines, such
as monocyte chemoattractant protein-4 (MCP-4) ⁄ CCL13, pulmonary and
activation-regulated chemokine (PARC) ⁄ CCL18, monokine induced
by interferon-c (Mig)⁄ CXCL9, stromal cell-derived factor 1 (SDF-1) ⁄
CXCL12, monocyte chemotactic protein 1 (MCP-1) ⁄ CCL2, macrophage
inflammatory protein 1a (MIP-1a) ⁄ CCL3, and Fractalkine ⁄ CXC3CL1.
Therefore, chemokines and chemokine-receptors are considered to be
important molecules in RA pathology.
Abbreviations
CCL3L1, CCL3-like 1; GROa, growth-related oncogene a; IFN-c, interferon-c; IL, interleukin; IP-10, interferon-c-inducible protein-10; MAPK,
mitogen-activated protein kinase; MCP, monocyte chemoattractant protein; Mig, monokine induced by interferon-c; MIP, macrophage
inflammatory protein; MMP, matrix metalloproteinase; OA, osteoarthritis; PARC, pulmonary and activation-regulated chemokine;
RA, rheumatoid arthritis; RANTES, regulated on activation, normal, T-cell expressed, and secreted; SDF, stromal cell-derived factor;
TNF-a, tumor necrosis factor-a.
4448 FEBS Journal 275 (2008) 4448–4455 ª 2008 The Authors Journal compilation ª 2008 FEBS
inflammatory disorders such as RA. Based on a number
of recently published studies, this review focuses on the
chemokines expressed in RA synovial tissues.
Chemokines
In humans there are more than 50 types of chemokines
– small (8–10 kDa) heparin-binding proteins – that
were originally identified by their chemotactic activity
on bone marrow-derived cells [3]. They are classified
into four families according to the location of cysteine
residues. The four chemokine groups are CC, C, CXC
and CX3C, where C is a cysteine and X any amino-
acid residue, and their receptors are consequently clas-
sified as CCR, CR, CXCR and CX3CR. The chemokine
receptors are bound to the cell membrane through
seven transmembrane helical segments coupled to a

G-protein that transduces the intracellular signal. The
two major subclasses include the CC chemokines
(where the cysteines are neighboring) and the CXC
chemokines (where the cysteines are separated by one
amino acid). The CXC chemokines mainly act on neu-
trophils and lymphocytes, whereas the CC chemokines
mainly act on monocytes and lymphocytes without
affecting neutrophils [4]. Lymphotactin, in the C
chemokine family, is similar to members of both the
CC and CXC chemokine families, but lacks two of the
four cysteine residues and is a potent attractant for
T cells, but not for monocytes or neutrophils [5]. Frac-
talkine, in the CX3C family, is a cell-surface-bound
protein, in which the first two cysteine residues are
separated by three amino acids, and has potent chemo-
attractant activity for T cells and monocytes [6]. One
characteristic feature of chemokines is the redundancy
of the system. Several chemokines bind to more than
one receptor, and the majority of chemokine receptors
have multiple ligands, leading to the generation of
multiple pathways directing similar cellular responses.
Until recently, chemokines have been named ran-
domly, with no clear system being used. Some have
been included with the interleukins [for example, inter-
leukin (IL)-8], and others have been given names
describing a function, for example, macrophage
chemoattractant proteins. In an attempt to clarify the
confused and complex nomenclature associated with
chemokines, the nomenclature of the chemokine
system has been revised. The name referring to a

specific biologic function has been replaced by the
chemokine subfamily name followed by a number [for
example, monocyte chemoattractant protein (MCP)-1
is CCL2] [7,8].
Synovial tissue and synovial fluid from RA patients
contain increased concentrations of several chemokines
(Table 1) [9,10]. The inflammatory cells that infiltrate
into RA synovial tissue express chemokine receptors,
including CXCR3, CCR5, CCR3, CCR2 and CXCR2
[11]. Based on these data, the chemokine system is
considered to be implicated in RA pathogenesis via the
recruitment and retention of monocytes and T lympho-
cytes into the joints [9,12]. Although macrophages and
FLS are considered to be the most potent producers of
chemokines in the synovial compartment, chondrocytes
also have the ability to produce chemokines [13–16].
Chemokine production is known to be induced at high
levels in response to inflammatory stimuli, such as
lipopolysaccharide, IL-1b, tumor necrosis factor-a
(TNF-a) and interferon-c (IFN-c) (Fig. 1).
Chemokine expression in the RA joint
CC chemokines
Monocyte chemoattractant protein-1 ⁄ CCL2 (a ligand
of CCR2) can attract monocytes, T cells, natural killer
cells and basophils [17,18]. Monocyte chemoattractant
protein-1 ⁄ CCL2 is highly expressed in synovial tissue
and synovial fluid in RA patients, and synovial tissue
macrophages are the dominant source of MCP-1 ⁄
CCL2 production [19]. The levels of MCP-1 ⁄ CCL2
correlate significantly with the levels of IL-1b, IL-6

and IL-8 ⁄ CXCL8 in culture supernatants of synovium
from RA patients, and the expression of MCP-1 ⁄
CCL2 mRNA by cultured synovial cells is stimulated
by IL-1b and TNF-a [20]. We recently found that
angiotensin II activated nuclear factor-jB in FLS to
induce MCP-1 ⁄ CCL2 [21].
Table 1. Chemokines and chemokine receptors expressed in the
joint of RA patients.
Systemic
name
Common
name
Chemokine
receptors
CC chemokines
CCL2 MCP-1 CCR2
CCL3 MIP-1a CCR1, CCR5
CCL5 RANTES CCR1, CCR3, CCR5
CCL13 MCP-4 CCR2, CCR3
CCL18 PARC Unknown
CCL20 MIP-3a CCR6
CXC chemokines
CXCL1 GROa CXCR2
CXCL8 IL-8 CXCR1, CXCR2
CXCL9 Mig CXCR3
CXCL10 IP-10 CXCR3
CXCL12 SDF-1 CXCR4
C chemokine
XCL1 Lymphotactin XCR1
CX3C chemokine

CX3CL1 Fractalkine CX3CR1
T. Iwamoto et al. Chemokines in the joints of patients
FEBS Journal 275 (2008) 4448–4455 ª 2008 The Authors Journal compilation ª 2008 FEBS 4449
Regulated on activation, normal, T-cell expressed,
and secreted (RANTES) ⁄ CCL5 (a ligand of CCR1,
CCR3 and CCR5) is another CC chemokine, impli-
cated in RA pathogenesis, which is expressed and
secreted from normal T cells that are regulated upon
activation. Histological examination of affected rheu-
matoid joints reveals extensive RANTES ⁄ CCL5
expression in the synovial lining and sublining layers
[22]. The expression of RANTES ⁄ CCL5 in cultured
FLS increases in both a time-dependent and dose-
dependent manner upon stimulation with TNF-a and
IL-1b [23].
Macrophage inflammatory protein (MIP)-1a ⁄ CCL3
(a ligand of CCR1 and CCR5) levels are higher in RA
synovial fluid than in synovial fluid from other forms
of arthritis, including osteoarthritis (OA). Isolated FLS
produce MIP-1a ⁄ CCL3 mRNA and protein upon
incubation with lipopolysaccharide and TNF-a [24].
Freshly isolated synovial fluid neutrophils also contain
higher concentrations of MIP-1a ⁄ CCL3 protein than
peripheral blood neutrophils from either RA patients
or healthy controls, and incubation in the presence
of TNF-a results in an increase in MIP-1a ⁄ CCL3
secretion by neutrophils in the synovial fluid of RA
patients [25].
Macrophage inflammatory protein-3a ⁄ CCL20 (a
ligand of CCR6) is a selective chemoattractant for

leucocytes such as memory T cells, naive B cells and
immature dendritic cells. Macrophage inflammatory
protein-3a ⁄ CCL20 is highly expressed in synovial flu-
ids and synovial tissue specimens of patients with RA,
and cultured FLS derived from either RA or OA
patients are capable of producing MIP-3a ⁄ CCL20 in
response to IL-1b and TNF-a in vitro [26]. Increased
expression of MIP-3a ⁄ CCL20 and CCR6 has also been
confirmed in tissue biopsies from RA subchondral
bone [27].
Our group recently found that the mRNA exp-
ression of MCP-4 ⁄ CCL13 (a ligand of CCR2 and
CCR3), which is the major chemoattractant for eosin-
ophils, monocytes and T lymphocytes, is significantly
higher in cartilage from RA patients than in cartilage
from OA patients or normal controls. Furthermore,
the concentration of MCP-4 ⁄ CCL13 protein in syno-
vial fluid is also significantly higher in RA patients
than in OA patients [28]. Monocyte chemoattractant
protein-4 ⁄ CCL13 production in cultured human chon-
drocytes is stimulated by IFN-c in combination with
IL-1b or TNF-a [13].
We also found that pulmonary and activation-regu-
lated chemokine (PARC)⁄ CCL18 is expressed more
strongly in RA cartilage and synovial membrane than
in OA samples. The levels of PARC ⁄ CCL18 in serum
and synovial fluid are also higher in RA patients than
in OA patients and normal controls. In addition, the
levels of PARC ⁄ CCL18 in serum significantly correlate
with the levels of rheumatoid factor [14].

Cartilage
Cartilage
RA joint
TNF-α, IL-1β, IFN-γ
A
B
Synoviocytes
Macrophage
T cell
Chemokines
RA joint
Chemotaxis
Chemokines
Synovial hyperplasia
MMP release
Angiogenesis
Pannus formation
Fig. 1. Schematic representation of the role of chemokines in the
joint of RA patients. (A) Synovial macrophages, T cells, synovio-
cytes and also chondrocytes produce various chemokines stimu-
lated mainly by inflammatory cytokines, including IL-1b, TNF-a and
IFN-c. (B) Chemokines expressed in the joint recruit leukocytes into
the joints. In addition to functioning in cell trafficking, several
chemokines have other biological abilities. Chemokines stimulate
FLS and chondrocytes to release inflammatory mediators, including
cytokines and MMPs, leading to cartilage degradation and pannus
formation. Furthermore, chemokines enhance cell proliferation and
angiogenesis, leading to synovial hyperplasia. Chemokines released
by leukocytes and FLS, or by the chondrocytes themselves, can
induce autocrine ⁄ paracrine stimulation of these cells, leading to

joint destruction.
Chemokines in the joints of patients T. Iwamoto et al.
4450 FEBS Journal 275 (2008) 4448–4455 ª 2008 The Authors Journal compilation ª 2008 FEBS
CXC chemokines
Interleukin-8 ⁄ CXCL8 (a ligand of CXCR1 and
CXCR2) was the first chemokine identified to be
involved in leukocyte chemotaxis [29]. Interleukin-8 ⁄
CXCL8 is present in high quantities in both the
synovial tissue and synovial fluid of RA patients,
and synovial tissue macrophages constitutively pro-
duce IL-8 ⁄ CXCL8 [30]. Interleukin-8 ⁄ CXCL8 is
known to have angiogenic activity in the RA joint
[31]. Strong induction of IL-8 ⁄ CXCL8 is also
observed in primary cultures of articular chondro-
cytes as well as in cartilage explants stimulated with
IL-1b [32].
Growth-related oncogene a (GROa) ⁄ CXCL1 (a
ligand of CXCR2), a chemoattractant for neutrophils,
similarly to IL-8⁄ CXCL8, is highly expressed in syno-
vial fluid and synovial tissue in RA patients. Further-
more, the production of GROa ⁄ CXCL1 by RA FLS
and chondrocytes is significantly increased upon incu-
bation with TNF-a or IL-1b [16,33,34]. Interleukin-17
also induces the expression of GRO a ⁄ CXCL1 mRNA,
as well as the expression of IL-8⁄ CXCL8 mRNA,
which is dependent on p38 mitogen-activated protein
kinase (MAPK) in RA FLS [35]. Growth-related onco-
gene a ⁄ CXCL1 induces a dose-dependent decrease in
the expression of interstitial collagens by rheumatoid
synovial fibroblasts [36].

Interferon-c-inducible protein-10 (IP-10) ⁄ CXCL10 (a
ligand of CXCR3) is also upregulated in RA synovial
fluid and synovial tissue [9,37]. Immunolocalization
analysis indicated that IP-10 ⁄ CXCL10 is associated
mainly with infiltrating macrophage-like cells and
fibroblast-like cells in the RA synovium, and the inter-
action of activated leukocytes with FLS results in
marked increases in the expression and secretion of
IP-10 ⁄ CXCL10 [37]. Human chondrocytes also produce
IP-10 ⁄ CXCL10 stimulated by the pro-inflammatory
cytokines IL-1b or TNF-a [38].
Monokine induced by interferon-c (Mig) ⁄ CXCL9,
also a ligand of CXCR3, is highly expressed in RA
synovial fluid and synovial tissue, particularly in
macrophages [9]. The expression of Mig ⁄ CXCL9 by
cultured FLS is stimulated by IFN-c [39].
Stromal cell-derived factor (SDF)-1 ⁄ CXCL12, a
ligand of CXCR4, is expressed in the RA synovium
and is increased by CD40 stimulation [40]. Stromal
cell-derived factor-1 ⁄ CXCL12 stimulates the migration
of CD4
+
memory T cells in the RA synovium and
also inhibits activation-induced apoptosis of T cells,
indicating that SDF-1 ⁄ CXCR4 interactions play
important roles in CD4
+
memory T-cell accumulation
in the RA synovium [40].
C and CX3C chemokines

The C chemokine family is represented by two chemo-
kines (lymphotactin ⁄ XCL1 and SCM-1b ⁄ XCL2),
whereas the CX3C chemokine family contains only
one member, called fractalkine⁄ CX3CL1 [41]. The
levels of lymphotactin ⁄ XCL1 are significantly higher in
synovial fluid of RA patients than those in paired
serum samples. Expression of XCR1, a lymphotactin ⁄
XCL1 receptor, was detected in infiltrating mono-
nuclear cells and FLS of synovial tissues [42].
Fractalkine ⁄ CX3CL1, a chemoattractant for mono-
cytes and lymphocytes, is significantly elevated in RA
synovial fluid compared with synovial fluid from
patients with OA or other forms of arthritis. The syno-
vial fluid and peripheral blood of patients with RA
contain a greater percentage of monocytes expressing
fractalkine ⁄ CX3CL1 and CX3CR1 compared with
T cells [43]. Recombinant human fractalkine⁄ CX3CL1
significantly induces the migration of human dermal
microvascular endothelial cells, suggesting that it may
mediate angiogenesis in RA [44]. The secretion of frac-
talkine ⁄ CX3CL1 from FLS obtained from RA patients
is regulated mainly by TNF-a.
The role of chemokines in RA pathogenesis
The chemokines listed above are implicated in RA
pathogenesis via the recruitment and retention of leu-
kocytes in the joints. In addition to functioning in cell
trafficking, several chemokines have been shown to
possess other biological abilities [45].
Chemokines are able to stimulate FLS and chon-
drocytes to release inflammatory mediators, including

cytokines and matrix metalloproteinases (MMPs),
leading to cartilage degradation. Stimulation of RA
FLS with MCP-1 ⁄ CCL2, RANTES ⁄ CCL5 and SDF-
1 ⁄ CXCL12 results in the enhanced production of
IL-6 and IL-8 ⁄ CXCL8 [46]. Monocyte chemoattractant
protein-1 ⁄ CCL2, SDF-1 ⁄ CXCL12, IP-10 ⁄ CXCL10,
RANTES ⁄ CCL5 and Mig ⁄ CXCL9 increase, in a
dose-dependent and time-dependent manner, the gela-
tinase and collagenase activities in the supernatants
of cultured FLS [47]. Monocyte chemoattractant pro-
tein-1 ⁄ CCL2 and RANTES ⁄ CCL5 stimulate MMP-3
production by chondrocytes and are also able to
inhibit proteoglycan synthesis and to enhance proteo-
glycan release from the chondrocytes [48,49]. RAN-
TES ⁄ CCL5 induces the expression of inducible nitric
oxide synthase, IL-6 and MMP-3 in chondrocytes
[50]. The release of MMP-3 is also increased by
stimulating chondrocytes with SDF-1 ⁄ CXCL12 [10].
The interaction of SDF-1 ⁄ CXCL12 with CXCR4-
T. Iwamoto et al. Chemokines in the joints of patients
FEBS Journal 275 (2008) 4448–4455 ª 2008 The Authors Journal compilation ª 2008 FEBS 4451
positive chondrocytes results in a specific increase in
the release of MMP-3 [10]. Pathological concentra-
tions of SDF-1 ⁄ CXCL12 induce the death of human
chondrocytes and this is dependent on the p38
MAPK activity [51]. Lymphotactin ⁄ XCL1 stimulation
of RA FLS results in a marked downregulation of
MMP-2 production [52]. Thus, chemokines released
by mononuclear cells and FLS, or by the chondro-
cytes themselves, can induce an autocrine ⁄ paracrine

stimulation of these cells, leading to extracellular
matrix degradation.
Furthermore, chemokines have the ability to enhance
cell proliferation, leading to synovial hyperplasia.
Stimulation with MCP-1 ⁄ CCL2, SDF-1 ⁄ CXCL12,
IP-10 ⁄ CXCL10, Mig ⁄ CXCL9 and MCP-4 ⁄ CCL13
enhances the proliferation of FLS [13,47]. Our group
reported that the proliferation of FLS by MCP-
4 ⁄ CCL13 is dependent on activation of the extracellu-
lar regulated kinase MAPK. The activation of MAPK
is also important in regulating the RA FLS cytoskeletal
structure and migration by fractalkine ⁄ CX3CL1 [53].
Fractalkine ⁄ CX3CL1 was expressed on FLS, and
senescent CD28
)
T cells were positive for CX
3
CR1,
the receptor for fractalkine ⁄ CX3CL1. Fractalkine ⁄
CX3CL1 was expressed on FLS costimulated T-cell-
activating signals and amplified the proliferation,
IFN-c production and expulsion of cytoplasmic gran-
ules [54]. In addition, fractalkine ⁄ CX3CL1 not only
regulated T-cell function, but directly affected FLS pro-
liferation, suggesting that T-cell ⁄ FLS interactions led
to an autocrine growth-promoting loop enhancing the
proliferative expansion of FLS [55].
Chemokines also have either angiogenic or angio-
static abilities, which are important aspects of RA
synovium proliferation. Chemokines containing the

ELR motif, which is the three-amino-acid sequence
(Glu–Leu–Arg) near the N-terminus before the first
cysteine, are thought to be angiogenic, whereas chemo-
kines lacking the ELR motif mainly appear to be
angiostatic [45,56]. Interleukin-8 ⁄ CXCL8 was the first
chemokine identified to have angiogenic properties in
addition to chemoattractant effects [31]. Continuous
infusion of human recombinant IL-8 ⁄ CXCL8 into the
knee joints of rabbits for 14 days led to severe arthritis
characterized by apparent erythema and joint pain,
accumulation of leucocytes, infiltration of mononuclear
cells in synovial tissue and marked hypervascular-
ization in the synovial lining layer [57]. Other ELR-
containing CXC chemokines with angiogenic features
include GROa ⁄ CXCL1, whereas non-ELR chemo-
kines, such as Mig ⁄ CXCL9 and IP-10 ⁄ CXCL10, are
angiostatic. There are some exceptions to this rule as
certain chemokines lacking the ELR motif, including
MCP-1 ⁄ CCL2, SDF-1 ⁄ CXCL12 and fractalkine ⁄
CX3CL1, are also known to have angiogenic proper-
ties [44,58,59]. Recently, associations between the
chemokine gene polymorphisms and RA have been
investigated. An allelic variant in the 3¢-untranslated
region of the SDF-1 gene is associated with the annual
rates of radiographic progression, but not with suscep-
tibility to RA. However, the functional role of these
variants has not been clearly established thus far [60].
A recent meta-analysis reported a significant, negative
association of a 32-bp deletion in the CCR5 gene
(CCR5D32), which results in a nonfunctional receptor,

with susceptibility to RA, suggesting that CCR5D32
is protective against the development of RA [61].
The gene copy number variations of CCL3-like 1
(CCL3L1), a nonallelic isoform of CCL3 encoded by
different genes and a potent ligand for CCR1 and
CCR5, influenced susceptibility to RA, and genetic
interaction between CCL3L1 dose and CCR5D32 was
also found [62]. These results indicate that the genetic
variations of chemokines and chemokine receptors are
associated with RA susceptibility and severity.
Conclusion
Chemokines have an important role in the patho-
genesis of RA by recruiting leukocytes and by control-
ling other important processes, such as release of
mediators of inflammation, cell proliferation and
angiogenesis. To date, several animal studies and
human studies have shown the biological efficacy of
specific antagonism of ligands and receptors in RA
[45,63]. Thus, chemokines are key molecules in the
pathogenesis of RA, and chemokine targeting has
significant promise as an anti-RA strategy.
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