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-

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

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

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

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

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

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

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,

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