There-fore, chemokines and chemokine receptors are consid-ered to be therapeutic targets in several chronic Keywords chemokine receptors; chemokines; monocyte chemoattractant protein-4 M
Trang 1Molecular aspects of rheumatoid arthritis: chemokines
in the joints of patients
Takuji Iwamoto1,2, Hiroshi Okamoto1, Yoshiaki Toyama2and Shigeki Momohara1
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: hokamoto@ior.twmu.ac.jp
(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.
Trang 2inflammatory 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
CXC chemokines
C chemokine
CX3C chemokine
Trang 3Regulated 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 chondrosynovio-cytes 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.
Trang 4CXC 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 synosyno-vial 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 GROa⁄ 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 lymphomono-cytes, 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
Trang 5CXCR4-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 CX3CR1,
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
References
1 Tak PP & Bresnihan B (2000) The pathogenesis and prevention of joint damage in rheumatoid arthritis: advances from synovial biopsy and tissue analysis Arthritis Rheum 43, 2619–2633
2 Szekanecz Z, Szucs G, Szanto S & Koch AE (2006) Chemokines in rheumatic diseases Curr Drug Targets
7, 91–102
3 Charo IF & Ransohoff RM (2006) The many roles of chemokines and chemokine receptors in inflammation
N Engl J Med 354, 610–621
4 Luster AD (1998) Chemokines–chemotactic cytokines that mediate inflammation N Engl J Med 338, 436–445
5 Kelner GS, Kennedy J, Bacon KB, Kleyensteuber S, Largaespada DA, Jenkins NA, Copeland NG, Bazan
JF, Moore KW, Schall TJ et al (1994) Lymphotactin:
Trang 6a cytokine that represents a new class of chemokine.
Science 266, 1395–1399
6 Bazan JF, Bacon KB, Hardiman G, Wang W, Soo K,
Rossi D, Greaves DR, Zlotnik A & Schall TJ (1997) A
new class of membrane-bound chemokine with a CX3C
motif Nature 385, 640–644
7 Zlotnik A & Yoshie O (2000) Chemokines: a new
classi-fication system and their role in immunity Immunity
12, 121–127
8 Bacon K, Baggiolini M, Broxmeyer H, Horuk R,
Lindley I, Mantovani A, Maysushima K, Murphy P,
Nomiyama H, Oppenheim J et al (2002) Chemokine⁄
chemokine receptor nomenclature J Interferon Cytokine
Res 22, 1067–1068
9 Patel DD, Zachariah JP & Whichard LP (2001)
CXCR3 and CCR5 ligands in rheumatoid arthritis
synovium Clin Immunol 98, 39–45
10 Kanbe K, Takagishi K & Chen Q (2002) Stimulation of
matrix metalloprotease 3 release from human
chondro-cytes by the interaction of stromal cell-derived factor 1
and CXC chemokine receptor 4 Arthritis Rheum 46,
130–137
11 Szekanecz Z, Kim J & Koch AE (2003) Chemokines
and chemokine receptors in rheumatoid arthritis Semin
Immunol 15, 15–21
12 Katschke KJ Jr, Rottman JB, Ruth JH, Qin S, Wu L,
LaRosa G, Ponath P, Park CC, Pope RM & Koch AE
(2001) Differential expression of chemokine receptors
on peripheral blood, synovial fluid, and synovial tissue
monocytes⁄ macrophages in rheumatoid arthritis
Arthritis Rheum 44, 1022–1032
13 Iwamoto T, Okamoto H, Kobayashi S, Ikari K,
Toyama Y, Tomatsu T, Kamatani N & Momohara S
(2007) A role of monocyte chemoattractant protein-4
(MCP-4)⁄ CCL13 from chondrocytes in rheumatoid
arthritis FEBS J 274, 4904–4912
14 Momohara S, Okamoto H, Iwamoto T, Mizumura T,
Ikari K, Kawaguchi Y, Takeuchi M, Kamatani N &
Tomatsu T (2007) High CCL18⁄ PARC expression in
articular cartilage and synovial tissue of patients with
rheumatoid arthritis J Rheumatol 34, 266–271
15 Villiger PM, Terkeltaub R & Lotz M (1992) Production
of monocyte chemoattractant protein-1 by inflamed
synovial tissue and cultured synoviocytes J Immunol
149, 722–727
16 Hosaka S, Akahoshi T, Wada C & Kondo H (1994)
Expression of the chemokine superfamily in rheumatoid
arthritis Clin Exp Immunol 97, 451–457
17 Loetscher P, Seitz M, Clark-Lewis I, Baggiolini M &
Moser B (1994) Monocyte chemotactic proteins MCP-1,
MCP-2, and MCP-3 are major attractants for human
CD4+ and CD8+ T lymphocytes FASEB J 8, 1055–
1060
18 Iikuni N, Okamoto H, Yoshio T, Sato E, Kamitsuji S,
Iwamoto T, Momohara S, Taniguchi A, Yamanaka H,
Minota S et al (2006) Raised monocyte chemotactic protein-1 (MCP-1)⁄ CCL2 in cerebrospinal fluid of patients with neuropsychiatric lupus Ann Rheum Dis
65, 253–256
19 Koch AE, Kunkel SL, Harlow LA, Johnson B, Evanoff
HL, Haines GK, Burdick MD, Pope RM & Strieter
RM (1992) Enhanced production of monocyte chemo-attractant protein-1 in rheumatoid arthritis J Clin Invest 90, 772–779
20 Harigai M, Hara M, Yoshimura T, Leonard EJ, Inoue
K & Kashiwazaki S (1993) Monocyte chemoattractant protein-1 (MCP-1) in inflammatory joint diseases and its involvement in the cytokine network of rheumatoid synovium Clin Immunol Immunopathol 69, 83–91
21 Iikuni N, Okamoto H, Kasahara M & Kamatani N (2005) An angiotensin receptor blocker suppresses monocyte chemoattractant protein 1 production from rheumatoid synovial fibroblasts: comment on the article
by Sagawa et al Arthritis Rheum 52, 4047–4048
22 Robinson E, Keystone EC, Schall TJ, Gillett N & Fish
EN (1995) Chemokine expression in rheumatoid arthri-tis (RA): evidence of RANTES and macrophage inflam-matory protein (MIP)-1 beta production by synovial
T cells Clin Exp Immunol 101, 398–407
23 Rathanaswami P, Hachicha M, Sadick M, Schall TJ & McColl SR (1993) Expression of the cytokine RANTES
in human rheumatoid synovial fibroblasts Differential regulation of RANTES and interleukin-8 genes by inflammatory cytokines J Biol Chem 268, 5834–5839
24 Koch AE, Kunkel SL, Harlow LA, Mazarakis DD, Haines GK, Burdick MD, Pope RM & Strieter RM (1994) Macrophage inflammatory protein-1 alpha A novel chemotactic cytokine for macrophages in rheuma-toid arthritis J Clin Invest 93, 921–928
25 Hatano Y, Kasama T, Iwabuchi H, Hanaoka R, Takeuchi HT, Jing L, Mori Y, Kobayashi K, Negishi
M, Ide H et al (1999) Macrophage inflammatory protein 1 alpha expression by synovial fluid neutrophils
in rheumatoid arthritis Ann Rheum Dis 58, 297–302
26 Matsui T, Akahoshi T, Namai R, Hashimoto A, Kurihara Y, Rana M, Nishimura A, Endo H, Kitasato
H, Kawai S et al (2001) Selective recruitment of CCR6-expressing cells by increased production of MIP-3 alpha in rheumatoid arthritis Clin Exp Immunol
125, 155–161
27 Lisignoli G, Piacentini A, Cristino S, Grassi F, Cavallo
C, Cattini L, Tonnarelli B, Manferdini C & Facchini A (2007) CCL20 chemokine induces both osteoblast pro-liferation and osteoclast differentiation: increased levels
of CCL20 are expressed in subchondral bone tissue of rheumatoid arthritis patients J Cell Physiol 210, 798– 806
28 Iwamoto T, Okamoto H, Iikuni N, Takeuchi M, Toyama Y, Tomatsu T, Kamatani N & Momohara S (2006) Monocyte chemoattractant protein-4 (MCP-4)⁄
Trang 7CCL13 is highly expressed in cartilage from patients
with rheumatoid arthritis Rheumatology (Oxford) 45,
421–424
29 Baggiolini M, Walz A & Kunkel SL (1989)
Neutrophil-activating peptide-1⁄ interleukin 8, a novel cytokine that
activates neutrophils J Clin Invest 84, 1045–1049
30 Koch AE, Kunkel SL, Burrows JC, Evanoff HL,
Haines GK, Pope RM & Strieter RM (1991) Synovial
tissue macrophage as a source of the chemotactic
cyto-kine IL-8 J Immunol 147, 2187–2195
31 Koch AE, Polverini PJ, Kunkel SL, Harlow LA,
DiPietro LA, Elner VM, Elner SG & Strieter RM
(1992) Interleukin-8 as a macrophage-derived mediator
of angiogenesis Science 258, 1798–1801
32 Recklies AD & Golds EE (1992) Induction of synthesis
and release of interleukin-8 from human articular
chon-drocytes and cartilage explants Arthritis Rheum 35,
1510–1519
33 Koch AE, Kunkel SL, Shah MR, Hosaka S, Halloran
MM, Haines GK, Burdick MD, Pope RM & Strieter
RM (1995) Growth-related gene product alpha A
chemotactic cytokine for neutrophils in rheumatoid
arthritis J Immunol 155, 3660–3666
34 Pulsatelli L, Dolzani P, Piacentini A, Silvestri T,
Ruggeri R, Gualtieri G, Meliconi R & Facchini A
(1999) Chemokine production by human chondrocytes
J Rheumatol 26, 1992–2001
35 Kehlen A, Thiele K, Riemann D & Langner J (2002)
Expression, modulation and signalling of IL-17 receptor
in fibroblast-like synoviocytes of patients with
rheuma-toid arthritis Clin Exp Immunol 127, 539–546
36 Unemori EN, Amento EP, Bauer EA & Horuk R
(1993) Melanoma growth-stimulatory activity⁄ GRO
decreases collagen expression by human fibroblasts
Regulation by C-X-C but not C-C cytokines J Biol
Chem 268, 1338–1342
37 Hanaoka R, Kasama T, Muramatsu M, Yajima N,
Shiozawa F, Miwa Y, Negishi M, Ide H, Miyaoka H,
Uchida H et al (2003) A novel mechanism for the
regu-lation of IFN-gamma inducible protein-10 expression in
rheumatoid arthritis Arthritis Res Ther 5, R74–R81
38 De Ceuninck F, Dassencourt L & Anract P (2004) The
inflammatory side of human chondrocytes unveiled by
antibody microarrays Biochem Biophys Res Commun
323, 960–969
39 Tsubaki T, Takegawa S, Hanamoto H, Arita N,
Kamogawa J, Yamamoto H, Takubo N, Nakata S,
Yamada K, Yamamoto S et al (2005) Accumulation of
plasma cells expressing CXCR3 in the synovial
sublin-ing regions of early rheumatoid arthritis in association
with production of Mig⁄ CXCL9 by synovial fibroblasts
Clin Exp Immunol 141, 363–371
40 Nanki T, Hayashida K, El-Gabalawy HS, Suson S, Shi
K, Girschick HJ, Yavuz S & Lipsky PE (2000) Stromal
cell-derived factor-1-CXC chemokine receptor 4
interac-tions play a central role in CD4+ T cell accumulation
in rheumatoid arthritis synovium J Immunol 165, 6590– 6598
41 Stievano L, Piovan E & Amadori A (2004) C and CX3C chemokines: cell sources and physiopathological implications Crit Rev Immunol 24, 205–228
42 Wang CR, Liu MF, Huang YH & Chen HC (2004) Up-regulation of XCR1 expression in rheumatoid joints Rheumatology (Oxford) 43, 569–573
43 Ruth JH, Volin MV, Haines GK 3rd, Woodruff DC, Katschke KJ Jr, Woods JM, Park CC, Morel JC & Koch AE (2001) Fractalkine, a novel chemokine in rheumatoid arthritis and in rat adjuvant-induced arthri-tis Arthritis Rheum 44, 1568–1581
44 Volin MV, Woods JM, Amin MA, Connors MA, Harlow LA & Koch AE (2001) Fractalkine: a novel angiogenic chemokine in rheumatoid arthritis Am J Pathol 159, 1521–1530
45 Haringman JJ, Ludikhuize J & Tak PP (2004) Chemo-kines in joint disease: the key to inflammation? Ann Rheum Dis 63, 1186–1194
46 Nanki T, Nagasaka K, Hayashida K, Saita Y & Miyasaka N (2001) Chemokines regulate IL-6 and IL-8 production by fibroblast-like synoviocytes from patients with rheumatoid arthritis J Immunol 167, 5381–5385
47 Garcia-Vicuna R, Gomez-Gaviro MV, Dominguez-Luis
MJ, Pec MK, Gonzalez-Alvaro I, Alvaro-Gracia JM & Diaz-Gonzalez F (2004) CC and CXC chemokine receptors mediate migration, proliferation, and matrix metalloproteinase production by fibroblast-like synovio-cytes from rheumatoid arthritis patients Arthritis Rheum 50, 3866–3877
48 Borzi RM, Mazzetti I, Cattini L, Uguccioni M, Baggio-lini M & Facchini A (2000) Human chondrocytes express functional chemokine receptors and release matrix-degrading enzymes in response to C-X-C and C-C chemokines Arthritis Rheum 43, 1734–1741
49 Yuan GH, Masuko-Hongo K, Sakata M, Tsuruha J, Onuma H, Nakamura H, Aoki H, Kato T & Nishioka
K (2001) The role of C-C chemokines and their receptors in osteoarthritis Arthritis Rheum 44, 1056–1070
50 Alaaeddine N, Olee T, Hashimoto S, Creighton-Acher-mann L & Lotz M (2001) Production of the chemokine RANTES by articular chondrocytes and role in carti-lage degradation Arthritis Rheum 44, 1633–1643
51 Wei L, Sun X, Kanbe K, Wang Z, Sun C, Terek R & Chen Q (2006) Chondrocyte death induced by patholog-ical concentration of chemokine stromal cell-derived factor-1 J Rheumatol 33, 1818–1826
52 Blaschke S, Middel P, Dorner BG, Blaschke V, Hummel KM, Kroczek RA, Reich K, Benoehr P, Koziolek M & Muller GA (2003) Expression of activa-tion-induced T cell-derived, and chemokine-related
Trang 8cytokine⁄ lymphotactin and its functional role in
rheumatoid arthritis Arthritis Rheum 48, 1858–1872
53 Volin MV, Huynh N, Klosowska K, Chong KK &
Woods JM (2007) Fractalkine is a novel
chemoattrac-tant for rheumatoid arthritis fibroblast-like synoviocyte
signaling through MAP kinases and Akt Arthritis
Rheum 56, 2512–2522
54 Sawai H, Park YW, Roberson J, Imai T, Goronzy JJ &
Weyand CM (2005) T cell costimulation by
fractalkine-expressing synoviocytes in rheumatoid arthritis
Arthri-tis Rheum 52, 1392–1401
55 Sawai H, Park YW, He X, Goronzy JJ & Weyand CM
(2007) Fractalkine mediates T cell-dependent
prolifera-tion of synovial fibroblasts in rheumatoid arthritis
Arthritis Rheum 56, 3215–3225
56 Rossi D & Zlotnik A (2000) The biology of chemokines
and their receptors Annu Rev Immunol 18, 217–242
57 Endo H, Akahoshi T, Nishimura A, Tonegawa M,
Takagishi K, Kashiwazaki S, Matsushima K & Kondo
H (1994) Experimental arthritis induced by continuous
infusion of IL-8 into rabbit knee joints Clin Exp
Immunol 96, 31–35
58 Salcedo R, Wasserman K, Young HA, Grimm MC,
Howard OM, Anver MR, Kleinman HK, Murphy
WJ & Oppenheim JJ (1999) Vascular endothelial
growth factor and basic fibroblast growth factor
induce expression of CXCR4 on human endothelial cells: In vivo neovascularization induced by stromal-derived factor-1alpha Am J Pathol 154, 1125–1135
59 Salcedo R, Ponce ML, Young HA, Wasserman K, Ward JM, Kleinman HK, Oppenheim JJ & Murphy
WJ (2000) Human endothelial cells express CCR2 and respond to MCP-1: direct role of MCP-1 in angio-genesis and tumor progression Blood 96, 34–40
60 Joven B, Gonzalez N, Aguilar F, Santiago B, Galindo
M, Alcami J & Pablos JL (2005) Association between stromal cell-derived factor 1 chemokine gene variant and radiographic progression of rheumatoid arthritis Arthritis Rheum 52, 354–356
61 Prahalad S (2006) Negative association between the chemokine receptor CCR5-Delta32 polymorphism and rheumatoid arthritis: a meta-analysis Genes Immun 7, 264–268
62 McKinney C, Merriman ME, Chapman PT, Gow PJ, Harrison AA, Highton J, Jones PB, McLean L, O’Donnell JL, Pokorny V et al (2008) Evidence for an influence of chemokine ligand 3-like 1 (CCL3L1) gene copy number on susceptibility to rheumatoid arthritis Ann Rheum Dis 67, 409–413
63 Okamoto H & Kamatani N (2006) A CCR-5 antagonist inhibits the development of adjuvant arthritis in rats Rheumatology (Oxford) 45, 230–232