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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Front Biosci (Schol Ed). Author manuscript; available in PMC 2010 August 9.
Published in final edited form as:
PMCID: PMC2917905
NIHMSID: NIHMS205283

Chemokines and chemokine receptors in arthritis

Abstract

Chemokines are involved in leukocyte recruitment to inflammatory sites, such as the synovial tissue in rheumatoid arthritis (RA). There is a structural and a functional classification of chemokines. The former includes four groups: CXC, CC, C and CX3C chemokines. Chemokines may also be either inflammatory or homeostatic, however, these functions often overlap. Anti-chemokine and anti-chemokine receptor targeting may be therapeutically used in the future biological therapy of arthritis. Most data in this field have been obtained from animal models of arthritis as only very few human RA trials have been completed. However, it is very likely that various specific chemokine and chemokine receptor antagonists will be developed and administered to RA patients.

Keywords: Rheumatoid Arthritis, Chemokines, Chemokine Receptors, Targeting, Review

2. INTRODUCTION

In arthritis, leukocytes extravasate through the vascular endothelium into the synovial tissue. Numerous synovial chemotactic mediators termed chemokines and their receptors are involved in this process (110). Currently, there are more than 50 known chemokines and 19 chemokine receptors (2). Some of these chemokines and chemokine receptors are also involved in intense synovial angiogenesis, the formation of new capillaries from preexisting vessels (5,7,11). In rheumatoid arthritis (RA), pro-inflammatory chemokines overrule anti-inflammatory chemokines resulting in accelerated inflammation in the synovial tissue (111). Thus, non-specific or specific blockade of chemokines may attenuate synovitis (112).

In this chapter, we will briefly review the role of chemokines and chemokine receptors in the pathogenesis of arthritis. We will also summarize recent studies on either non-specific or specific chemokine and chemokine receptor targeting.

3. CHEMOKINES AND CHEMOKINE RECEPTORS IN ARTHRITIS

Chemokines have been classified into the CXC, CC, C and CX3C supergene families. The receptors for these chemokines have been termed accordingly as CXCR, CCR, CR and CX3CR (2,5,6,1316). Although each chemokine has its own traditional name, they are also considered as CXCL, CCL, XCL and CX3CL chemokine ligands (2,5,6,10) (Table 1). Apart from this structural classification, as some chemokines are primarily involved in the development of lymphoid tissues and lymphoid neogenesis, while others rather play a role in inflammation, chemokines have also been functionally classified into homeostatic and inflammatory subclasses (10).

Table 1
Chemokines and chemokine receptors relevant for inflammatory synovitis1

3.1. CXC chemokines in arthritis

In these chemokines, there are two conserved C residues separated by one unconserved amino acid (2,15). CXC chemokines chemoattract neutrophils, lymphocytes and monocytes into the synovium (10,16). These mediators are also involved in cell adhesion, leukocyte integrin expression and L-selectin shedding, cytoskeletal reorganization, neutrophil degranulation and phagocytosis, as well as the production of proteases, prostanoids and platelet-activating factor (5,15,17).

Interleukin-8(IL-8)/CXCL8, epithelial-neutrophil activating protein 78 (ENA-78)/CXCL5 and growth-related oncogene alpha (gro-alpha)/CXCL1 are considered as the most important inflammatory chemokines associated with arthritis. These chemokines are abundantly expressed in the sera, synovial fluids and synovial tissues of RA patients (1823). Synovial macrophages are major producers of IL-8/CXCL8, ENA-78/CXC5 and gro-alpha/CXCL1 (1922,24), however, synovial lining cells, fibroblasts and endothelial cells may also release these chemokines (1922,24,25). There is a relationship between the genetic code and function of these chemokines, as genes coding these chemokines are clustered on chromosome 4q12–13 and all three chemokines chemoattract primarily neutrophils (16). The regulation of IL-8/CXCL8 production by synovial fibroblasts is controlled by NF-kappa-B (26). As an IL-8/CXCL8 binding site was discovered on endothelial syndecan-3, this suggests a role of chemokine-syndecan interactions during leukocyte trafficking into the arthritic synovial tissue (27). An intraarticular injection of IL-8/CXCL8 induced synovial inflammation in rabbit knee joints (28). In the rat adjuvant-induced arthritis (AIA) model for RA, the development of arthritis was associated with abundant ENA-78/CXCL5 production in the sera and, later, in the joints of rats (29). Gro-alpha/CXCL1 also enhances collagen deposition by RA fibroblasts and thus synovial fibrosis (30).

Connective tissue activating protein III (CTAP-III)/CXCL7 is produced by platelets and it has been detected in RA sera and synovial tissue samples (31). This inflammatory chemokine stimulates the proliferation of synovial fibroblasts, extracellular matrix deposition and thus synovial fibrosis (2,31,32). Cytokines and growth factors including IL-1, fibroblast growth factors and epidermal growth factor act in concert with CTAP-III/CXCL7 during proteoglycan synthesis (31,32). This chemokine also induces angiogenesis (2,31,32).

There is also abundant production of granulocyte chemotacric protein 2 (GCP-2)/CXCL6 in RA (33). GCP-2/CXCL6 expression is up-regulated on RA synovial fibroblasts via Toll-like receptor 2 (TLR2) signaling pathways (33).

Interferon-gamma-inducible protein 10 (IP-10)/CXCL10, monokine induced by interferon-gamma (Mig)/CXCL9 and platelet factor 4 (PF4)/CXCL4 exert pro-inflammatory, but anti-angiogenic effects in RA (2,17,3436). These chemokines have been detected in the sera. Synovial macrophages and fibroblasts release these chemokines (3436). In contrast to other CXC chemokines described above, the genes of PF4/CXCL4 and IP-10/CXCL10 are located on different chromosomes, and these chemokines recruit lymphocytes and monocytes rather than neutrophils (15,16). The induction of IP-10/CXCL10 on synovial fibroblasts requires intercellular adhesion molecule 1 (ICAM-1) and beta2 integrins (35).

While other CXC chemokines described above have common receptors, stromal cell-derived factor 1(SDF-1)/CXCL12 is a specific ligand for CXCR4. SDF-1/CXCL12 is primarily a homeostatic chemokine involved in lymphoid organization, however, it has also been implicated in synovial inflammation and synovial lymphoid neogenesis (3739). SDF-1/CXCL12 is expressed by synovial endothelial cells and this chemokine induces strong integrin-mediated adhesion of T cells to ICAM-1 (40). T cells are also able to migrate beneath cultured RA synovial fibroblasts. This process is termed pseudoemperipolesis. SDF-1/CXCL12 has also been implicated in this process (37). In a SCID mouse model, this chemokine stimulated monocyte recruitment into human synovial tissue engrafted onto the mice (34). Synovial T cell adhesion to fibroblasts upregulate SDF-1/CXCL12 production. This process involves IL-17- and CD40-CD40 ligand-dependent mechanisms (41). SDF-1/CXCL12 binds to endothelial proteoglycans and thus it mediates integrin-dependent leukocyte transendothelial migration, osteoclastogenesis, the development of bone erosions and thus radiographic progression in RA (39,4244).

The crucial role of B cells in the pathogenesis of RA has been acknowledged in recent years (4547). Among homeostatic chemokines involved in B cell migration and lymphoid tissue organization, B-cell activating chemokme-1 (BCA-1)/CXCL13, the specific ligand for CXCR5, is also expressed by synovial fibroblasts, endothelial cells and follicular dendritic cells within the RA synovium (48).

CXCL16, the specific ligand for CXCR6, primarily mediates lymphocyte recruitment and lymph node organization Yet, large amounts of CXCL16 were detected in RA synovia (49,50). Both synovial macrophages and fibroblasts secrete CXCL16 (49,50). Monocytes begin to express CXCL16 upon differentiation into macrophages (51). In the SCID mouse chimera model, CXCL16 recruited human mononuclear cells to the engrafted human RA synovial tissues (50). CXCL16-mediated leukocyte extravasation into the synovial tissue involved MAP kinase (MAPK) pathways (50).

3.2. CC chemokines

Monocyte chemoattractant protein 1 (MCP-1)/CCL2, macrophage inflammatory protein 1-alpha (MIP-1-alpha)/CCL3 and Regulated upon Activation, Normal T-cell Expressed and Secreted (RANTES)/CCL5 exert chemotactic activity towards T cells, monocytes and natural killer (NK) cells (6,5254). All these chemokines have been detected in RA sera and synovia (19,35,5254). The synovial release of MCP-1/CCL2 and MIP-1-alpha/CCL3 may be further augmented by pro-inflammatory cytokines, such as TNF-alpha or IL-1 (19,53,55). Among other triggers, IL-18 also induces MCP-1/CCL2 production by macrophages (56). Hypoxia decreases (57), while TLR2 ligands stimulate MCP-1/CCL2 expression by synovial fibroblasts (33). The injection of MCP-1/CCL2 into rabbit knees induced arthritis (58). MCP-1/CCL2 has been implicated in TNF-mediated osteoclast differentiation of peripheral blood monocytes. Thus, this chemokine, similarly to SDF-1/CXCL12, is involved in periarticular bone resorption in arthritis (59). MIP-1-alpha/CCL3 production is augmented by TNF-alpha, IL-1 and IL-15 (60,61). A single nucleotide polymorphism (SNP) within the RANTES promoter gene promotes susceptibility to RA in Chinese patients (62).

MIP-3-alpha/CCL20, the specific ligand for CCR6, is chemotactic for monocytes and lymphocytes (2,63). RA synovial fibroblasts produce this chemokine in response to TNF-alpha, IL-1, IL-17 and IL-18 (6366). This chemokine has been implicated in the recruitment of IL-17-producing CCR6+ Th17 cells into the synovium (67). MIP-3-alpha/CCL2 induces both osteoblast proliferation and osteoclast differentiation. Furthermore, increased expression of this chemokine was detected in the subchondral bone of RA patients. MIP-3-alpha/CCL20 may collaborate with the RANK ligand system in the uncoupling between new bone formation and bone resorption in RA (68).

CCL18 facilitates T cell attraction by antigen-presenting cells. Serum CCL18 levels is increased in RA patients and correlate with disease activity in RA (69). Synovial fluid neutrophils release CCL18 during their recruitment into the joints (70).

MCP-4/CCL13 is expressed in the cartilage of the RA joint. The combination of IFN-gamma, TNF-alpha and IL-1 stimulate the release of MCP-4/CCL13 from arthritic chondrocytes. This chemokine stimulates synovial fibroblast proliferation (71).

Among primarily homeostatic CC chemokines, Epstein-Barr virus-induced gene 1 ligand chemokine (ELC)/CCL19 has also been detected in RA synovial tissues (40). Secondary lymphoid tissue chemokine (SLC)/CCL21 has been implicated in lymphoid neogenesis within the arthritic synovial tissue (48,72). Thymus and Activation Regulated Chemokine (TARC)/CCL17 and Pulmonary and Activation regulated Chemokine (PARC)/CCL18 also mediate T cell recruitment into the RA synovium (7375).

In a single recent study, MCP-2/CCL8, MCP-3/CCL7, hemofiltrate CC chemokine 1 (HCC-1)/CCL14, HCC-2/CCL15 and HCC-4/CCL16 have been detected in the RA synovium (76). The function of these chemokines in RA has not been fully elucidated. Chemokine-like factor 1 (CKLF1) is a functional ligand of CCR4. Its expression is up-regulated on activated CD4+ and CD8+ T cells in RA (77).

3.3. C and CX3C chemokines in RA

The C chemokine family contains two members, lymphotactin/XCL1 and single C motif 1-beta (SCM-1-beta)/XCL2 (5,6). Lymphotactin/XCL1 is involved in T cell chemotaxis and it has been detected on CD8+ and CD4+/CD28 T cells in RA (78). This chemokine stimulates T cell accumulation into the RA joint and down-regulates matrix metalloproteinase 2 (MMP-2) production by RA synovial fibroblasts (79).

The single member of the CX3C family is fractalkine/CX3CL1, which is chemotactic for monocytes, lymphocytes and it also serves as a CD4+ T cell adhesion molecule (8083). Fractalkine/CX3CL1 enhances the adhesion of senescent T cells to synovial fibroblasts. In addition, this chemokine provides survival signals for and costimulates the production of pro-inflammatory cytokines by these T cells (83). Fractalkine/CX3CL 1 regulates the cytoskeletal structure, proliferation and migration of synovial fibroblasts (84,85). The activity of this chemokine involves JNK, ERK-1/2 and Akt (85). RA synovial macrophages, fibroblasts, endothelial and dendritic cells produce fractalkine/CX3CL1 (81,83). Fractalkine/CX3CL 1 has been associated with disease activity in rheumatoid vasculitis (86), as well as with accelerated atherosclerosis and increased cardiovascular morbidity in RA (8789).

3.4. Chemokine receptors in arthritis

Chemokine receptors are 7-transmembrane domain receptors expressed on the target cells. Some chemokine receptors, such as CXCR2, CCR1 or CCR3 have multiple ligands, while others including CXCR4, CXCR5, CXCR6, CCR8 or CCR9 are specific receptors for one single ligand (2,6,16) (Table 1).

Generally all CXCRs have been associated with the pathogenesis of arthritis. CXCR1 and CXCR2 exert abundant expression in the RA synovium. These chemokine receptors recognize the most relevant inflammatory and angiogenic CXC chemokines described above (2,6). CXCR3 may be the most important receptor in leukocyte homing into the RA synovium (81,90,91). Most T cells in the RA synovial fluid express this chemokine receptor (92). The high expression of CXCR3 on synovial T cells has been associated with a high IFN-gamma/IL-4 ratio, suggesting a preferential Th1 over Th2 phenotype of these T cells (93). CXCR3 is also expressed on RA synovial endothelial and dendritic cells (90,94). CXCR4 is involved in SDF-1/CXCL12-dependent ingress of lymphocytes into the RA synovial tissue (39). CXCR5 is expressed by T, B cells, macrophages and endothelial cells (93) and it is involved in synovial lymphoid neogenesis underlying arthritis (95). CXCR6 mediates CXCL16-induced synovitis (50). CXCR4, CXCR5 and CXCR6 bind their respective homeostatic chemokine ligands, SDF-1/CXCL12, BCA-1/CXCL13 and CXCL16. Thus, these CXC chemokine receptors are involved in both homeostatic and inflammatory processes (2,10,39,50,96).

Among CC chemokine receptors, CCR1 and CCR5 are abundantly expressed in the RA synovium (76,81,91,97). These CCRs, as well as CCR2 and CCR3 are also present on articular chondrocytes (98). CCR4 has also been implicated in leukocyte ingress into the RA joint (94). In some studies, a SNP leading to the production of the truncated delta-32-CCR5 non-functional receptor allele was found to be protective against RA (99). However, this protective role could not be confirmed in other national cohorts (100,101). CCR6, the single receptor for MIP-3-alpha/CCL20 has also been detected on RA synovial leukocytes (63). CCR6 is involved in the ingress of Th17 arthritogenic lymphocytes into the joint (67). CCR7 has been associated with synovial lymphoid neogenesis in mice (95). A putative chemokine receptor, CCR-like receptor 2 (CCRL2) has been identified on RA synovial fluid neutrophils and macrophages (102). In comparative study on CCRs, peripheral blood monocytes mainly expressed CCR1 and CCR2 suggesting that these receptors were involved in monocyte recruitment from the circulation. In contrast, CCR3 and CCR5 expression were up-regulated in RA SF indicating that these CCRs were important in monocyte retention in the joint (97).

Regarding the C and CX3C chemokine receptors, XCR1 is expressed on RA synovial lymphocytes, macrophages and fibroblasts (2,6), while CX3CR1 has been detected on macrophages and dendritic cells (82). As described above, the fractalkine/CX3CL1-CX3CR1 system has been implicated in the pathogenesis of RA-associated atherosclerosis (8789) (see later).

4. FUNCTIONAL ASPECTS OF CHEMOKINES AND CHEMOKINE RECEPTORS IN SYNOVIAL INFLAMMATION

4.1. Inflammatory and homeostatic chemokines in RA

As described above, chemokines have been functionally classified into homeostatic and inflammatory subgroups, however, these functions often overlap (10). Homeostatic chemokines are constitutively produced in lymphoid or non-lymphoid tissues. Lymphoid neogenesis has been associated with arthritis leading to lymphoid aggregates and germinal center-like structures within the inflamed synovial tissue. The synovium, in many ways, is similar to the skin, as well as to other mucosa-associated lymphoid tissues (MALT) (10,48,96). Some primarily homeostatic chemokines including SDF-1/CXCL12, BCA-1/CXCL13, CXCL16, TARC/CCL17, PARC/CCL18, ELC/CCL19 and SLC/CCL21 may also be involved in synovial inflammation (10,39,40,48,50,96,103,104).

On the other hand, most CXC and CC chemokines, C and CX3C chemokines, as well as their respective receptors are primarily inflammatory chemokines (2,6,96). As described above, IL-8/CXCL8, ENA-78/CXCL5, gro-alpha/CXCL1, CTAP-III/CXCL7, IP-10/CXCL10, Mig/CXCL9, PF4/CXCL4, GCP-2/CXCL6, MCP-1/CCL2, MIP-1-alpha/CCL3, MIP-3-alpha/CCL20, RANTES/CCL5, lymphotactin/XCL1 and fractalkine/CX3CL1 are involved in leukocyte migration into the synovium (2,5,6,9,48,77).

4.2. The functional role of chemokine receptor expression patterns in inflammation

Certain chemokine receptor expression patterns have been associated with different types of chronic inflammation. For example, Th0-Th1 type inflammation observed in RA has been primarily associated with the abundant synovial expression of CXCR3 and CCR5. In contrast, asthma, a known Th2 type disease, rather involves CCR3, CCR4, CCR8 and their ligands (16,81,91,105).

4.3. Chemokines and chemokine receptors in synovial angiogenesis and RA-related atherosclerosis

RA has been associated with the perpetuation of synovial neovascularization dependent upon the imbalance between angiogenic and angiostatic mediators (1,3,5,8). Some chemokines and chemokine receptors may also promote or suppress synovial angiogenesis (3,5,8).

In general, CXC chemokines containing the ELR (Glu-Leu-Arg) amino acid motif are angiogenic, while those, lacking this sequence are rather angiostatic (5,17). As one exception to this rule, SDF-1/CXCL12 is ELR, nevertheless it still stimulates neovascularization (5,17). Among ELR+ CXC chemokines, IL-8/CXCL8, ENA-78/CXCL5, CTAP-III/CXCL7 and gro-alpha/CXCL1 are chemotactic for endothelial cells and they stimulate synovial angiogenesis (1,5,15,17,31,106). SDF-1/CXCL12 cooperates with the hypoxia-hypoxia-inducible factor (HIF)-vascular endothelial growth factor (VEGF) pathway, which plays a central role in the regulation of angiogenesis (103,107,108). SDF-1/CXCL12 expression has also been associated with tumor angiogenesis and its expression may serve as a prognostic marker in gliomas (109). The ELR IP-10/CXCL10, Mig/CXCL9 and PF4/CXCL4 are angiostatic (5,15,17,110112). IP-10/CXCL10 inhibits VEGF-dependent angiogenesis, in turn, VEGF induces endothelial expression of IP-10/CXCL10 (5,17,110,111). Thus, IP-10/CXCL10 may be an important regulator of VEGF-dependent synovial neovascularization (110,111).

Much less information has become available regarding the role of CC chemokines in synovial angiogenesis. For example, MCP-1/CCL2 induces endothelial cell chemotaxis and capillary formation via the CCR2 endothelial receptor (113,114). These effects involve the Ets-1 transcription factor, as well as integrins and ERK-1/2 (114). Myeloid progenitor inhibitory factor 1 (MPIF-1)/CCL23 has also been implicated in endothelial cell migration and angiogenesis (115). In contrast, the homeostatic chemokine SLC/CCL21 inhibits tumor progression and angiogenesis (116).

Chemokine receptors recognizing the most relevant angiogenic chemokine ligands described above exert inflammatory and angiogenic properties in RA. CXCR2 may be the most important chemokine receptor implicated in synovial angiogenesis as CXCR2 is a receptor for angiogenic, ELR+ CXC chemokines described above (5,98,113). CXCR4 is involved in SDF-1/CXCL12-mediated synovial neovascularization (39,117). Hypoxia induces CXCR4 expression via the stimulation of HIF-1 and VEGF production (118). CXCR7 recognizing I-TAC/CXCL11 and SDF-1/CXCL12 may also be involved in synovial angiogenesis (119). CCR2 is a receptor for the angiogenic MCP-1/CCL2 (5,113). In a murine model of skeletal muscle injury, CCR2-deficient animals exerted delayed muscular angiogenesis and decreased VEGF production (120). In contrast to these angiogenic chemokine receptors, CXCR3, which binds the angiostatic chemokines IP-10/CXCL10 and Mig/CXCL9, may rather be involved in chemokine-mediated angiostasis (2,5,6,16,17).

Fractalkme/CX3CL1 and CX3CR1 have been implicated in arthritis-related angiogenesis, as well as atherosclerosis (82,87,89,121). Indeed, CX3CR1 expression on atherogenic CD4+/CD28 T cells correlated with vascular damage in RA (88). Moreover, CX3CR1-deficient mice develop lesser degree of atherosclerosis than do wild type animals (121). The M280/I249 SNP in the CX3CR1 gene has been associated with decreased cardiovascular risk in humans (87).

4.4. Regulation of chemokine production during leukocyte recruitment

There may be a temporal regulation of chemokine and chemokine receptor production in the inflamed synovium. When the temporal expression of CXC and CC chemokines was assessed in sera and joint homogenates of rats with AIA, the production of ENA-78/CXCL5 and MIP-1-alpha/CCL3 showed a very early increase, preceding clinical symptoms. The release of these “early” chemokines occurred parallel with neutrophil recruitment and the production of acute-phase reactants. In contrast, MCP-1/CCL2 was rather involved in the later phase of AIA (122). In rat AIA, CCR1 exerted high constitutive expression on macrophages throughout the disease course. CCR5 expression was up-regulated on synovial macrophages. CCR2 expression on endothelial cells was down-regulated during the progression of the disease. CCR3 expression on macrophages also decreased during the course of AIA. These results suggest that CCR2 and CCR5 may sustain inflammatory changes, while CCR2 and CCR3 may play a role in initial recruitment of leukocytes into the synovial tissue (123).

A regulatory network of pro-inflammatory cytokines and chemokines exists in the arthritic synovium (2,5,6,124,125). As discussed above, some cytokines including TNF-alpha, IL-1, IL-6, IL-15, IL-18 and others may enhance, while others rather suppress chemokine production (2,5,21,53,125). For example, IL-8/CXCL8 secretion by RA synovial fibroblasts is stimulated by IL-4 but inhibited by IFN-gamma. In contrast, RANTES/CCL5 production is suppressed by IL-4 but augmented by IFN-gamma (55). On the other hand, some chemokines may also influence cytokine production (2,5,6,29,126). For example, MIP-1-alpha/CCL3 stimulates the synthesis of TNF-alpha, IL-1 and IL-6 by synovial macrophages (5,126).

As described above, TLRs may also be involved in the regulation of chemokine function. TLR2 ligands activate synovial fibroblasts. Peptidoglycan, a TLR2 ligand, stimulated, among others, IL-8/CXCL8, Gro-alpha/CXCL1, MCP-1/CCL2, MIP-1-alpha/CCL3 and RANTES/CCL5 mRNA expression by these fibroblasts (33).

5. TARGETING OF CHEMOKTNES AND CHEMOKTNE RECEPTORS

Chemokines and chemokine receptors may be targeted by non-specific, as well as by chemokine-specinc approaches. These strategies have been tried in animal models of arthritis, in vitro cultures of human RA synovial cells and tissues, as well as in a very limited number of human RA clinical trials (2,5,6,9,127) (Table 1).

5.1. Non-specific agents

Some non-steroidal anti-inflammatory drugs, corticosteroids, traditional disease-modifying antirheumatic drugs (DMARD) and anti-TNF biologies exert multiple anti-inflammatory properties including chemokine inhibition. For example, diclofenac and meloxicam attenuated IL-8/CXCL8 production in the rat antigen-induced arthritis (AgIA) model (128). Dexamethasone, inhibited IL-8/CXCL8 and MCP-1/CCL2 release in RA patients (129). Among DMARDs, sulfasalazine inhibited the production of IL-8/CXCL8, MCP-1/CCL2 and gro-alpha/CXCL1 in cultured RA synovial tissue explants (130). Sulfapyridine inhibited the expression of IL-8/CXCL8 andMCP-1/CCL2 on cytokine-treated EC (131). In contrast, gold salts hardly had any effects on IL-8/CXCL8 or MCP-1/CCL2 synthesis (129). Methotrexate in combination with leflunomide suppressed MCP-1/CCL2 expression within the RA synovium (132). Methotrexate also suppressed the expression of CCR2 on RA peripheral blood monocytes. This effect correlated with lower disease activity (133). There have been increasing number of studies with anti-TNF agents. Infliximab suppressec IL-8/CXCL8, gro-alpha/CXCL1, CXCL16, MCP-1/CCL2 and RANTES/CCL5 production in RA (51,134137). Infliximab also reduced CCR3 and CCR5 expression on T cells in RA patients. The expression of these chemokine receptors was higher on non-responders than on responders (138). Treatment of RA patients with either infliximab or etanercept resulted in the clearance of CXCR3+ T cells from the synovium (139). Chemokine inhibition may have relevance for safety of anti-TNF therapy: infliximab reduced the secretion of IL-8/CXCL8, MIP-1-alpha/CCL3 and MCP-1/CCL2 in response to Mycobacteria. These authors suggest that the increased incidence of tuberculosis in infliximab-treated RA patients may be related, in part, to the inhibition of TNF-dependent chemokine gradients and impaired leukocyte migration (140).

Among other non-specific small molecule compounds, antioxidants including N-acetyl-L-cysteine and 2-oxothiazolidine-4-carboxylate, inhibited the expression of IL-8/CXCL8 and MCP-1/CCL2 mRNA by activated human synovial fibroblasts (141). Simvastatin inhibited IL-8/CXCL8 production by TNF-alpha-stimulated RA synovial fibroblasts (142). Triptolide, a diterpenoid triepoxide with potent anti-inflammatory effects, inhibited MCP-1/CCL2, MIP-1-alpha/CCL3 and RANTES/CCL5 production in the rat AIA model (143). Epigallocatechin-3-gallate (EGCG), a compound derived from green tea, suppressed ENA-78/CXCL5, gro-alpha/CXCL1 and RANTES/CCL5 production by IL-1-stimulated RA synovial fibroblasts (144). A recently developed dual cyclooxygenase-lipoxygenase inhibitor, ML3000, downregulated Mig/CXCL9, IP-10/CXCL10 and I-TAC/CXCL11 expression on RA synovial fibroblasts (145). Activation of peroxisome proliferator-activated receptor gamma (PPAR-gamma) suppresses MCP-1/CCL2 expression in monocytes (59). Thus, PPAR-gamma agonists, such as glitazones, may inhibit chemokine production.

5.2. Specific chemokine and chemokine receptor targeting

Neutralizing antibodies to IL-8/CXCL8 prevented arthritis in rabbits (146). In the rat AIA model, a neutralizing polyclonal anti-ENA-78/CXCL5 antibody administered intravenously prevented the onset of the disease, however, it failed to inhibit the progression of synovitis when administered therapeutically (29). The preventative administration of an anti-gro-alpha/CXCL1 antibody delayed the onset and severity of collagen-induced arthritis (CIA) in mice (147). A synthetic peptide derived from PF4/CXCL4 inhibited the development of murine CIA (104). An antibody to CXCL16 suppressed synovitis and joint destruction in murine CIA (49). Passive immunization of mice with anti-MIP-1-alpha/CCL3 decreased the severity of murine CIA (147). A monoclonal antibody to MCP-1/CCL2 reduced synovitis in rat CIA (148). An anti-MCP-1/CCL2 antibody also prevented the recruitment of 111In-labeled T cells into the synovium in the rat model of streptococcal cell wall antigen (SCW)-induced arthritis (149). A novel inhibitor of endogenous MCP-1/CCL2, p8A-MCP-1, suppressed cytokine expression, synovial leukocyte infiltration, joint erosion and improved clinical signs of rat AIA (150). Another peptide inhibitor of MCP-1/CCL2 suppressed the development of arthritis in MRL-1pr mice (151). An anti-RANTES/CCL5 antibody inhibited the progression of murine CIA (152). KE-298, a combined MCP-1/CCL2 and RANTES/CCL5 inhibitor, attenuated the severity of rat AIA (153). A monoclonal antibody to fractalkme/CX3CL1 inhibited synovitis and joint destruction in murine CIA (154).

The efficacy of chemokine targeting may be increased by combining various specific strategies. For example, in murine AIA, a combination of MCP-1/CCL2 and gro-alpha/CXCL1 inhibition resulted in more pronounced effects than did MCP-1/CCL2 blockade alone (155). In the rabbit endotoxin-induced arthritis model, the combination of anti-IL-8/CXCL8 and anti-groa/CXCL1 antibodies inhibited knee arthritis better than did any of the two antibodies alone (156). Certainly, an increased toxicity using combined anti-chemokine strategies may be an important issue in the future (2).

Regarding chemokine receptor targeting, a nonpeptide oral antagonist of the CXCR2 receptor inhibited IL-8/CXCL-induced arthritis in rabbits (157). DF2162, an allosteric CXCR1/CXCR2 inhibitor diminished murine and rat arthritis (158,159). In the AIA model, an anti-CXCR3 antibody inhibited T cell recruitment and disease progression (160). Some small molecule CXCR4 antagonists gave promising results in arthritis studies (161). For example, AMD3100 inhibited CIA in I FN-gamma-deficient mice (162), while T140 analogs ameliorated murine CIA (163). Numerous CCR1 and CCR2 antagonists have been developed in recent years (164169). For example, J-113863, a small molecule CCR1 antagonist diminished synovitis and joint destruction in murine CIA (164). Met-RANTES, a dual CCR1/CCR5 antagonist, inhibited both murine CIA and rat AIA (170,171). Some anti-chemokine receptor effects may be dose-dependent. For example, while low doses of the MC-21 anti-CCR2 monoclonal antibody markedly improved murine CIA high doses of this antibody rather had pro-inflammatory effects (172).

Adenoviral gene transfer may also be a useful method in chemokine targeting. The vaccinia virus expresses a 35 kDa soluble protein (35k), which inactivates a number of CC chemokines. A recombinant adenovirus containing 35k reduced migration of CCR5-transfected cells in response to RANTES/CCL5. This vector also suppressed chemotaxis of both CCR5-transfected cells and primary macrophages in mice (173).

There have been only limited number of published human anti-chemokine or anti-chemokine receptor trials. An anti-MCP-1/CCL2 antibody, ABN912, has been introduced to a randomized, controlled human RA trial. In this study, 33 patients received the active compound, while 12 received placebo. Serial arthroscopic biopsies were performed. ABN912 treatment was well tolerated, but there was no detectable clinical benefit or significant change in synovial biomarkers (174). A small molecule CCR1 antagonist has been tried in a two-week phase Ib study. This inhibitor decreased the number of synovial macrophages. About one-third of the patients also fulfilled the ACR20 criteria for clinical improvement (166). CP-481,715, another CCR1 antagonist inhibited monocyte chemotactic activity present in human RA synovial fluid samples (165). This compound has been evaluated in phase I for pharmacokinetics and safety (175). Some CCR2 inhibitors have also entered clinical trials (168). Among CCR5 inhibitors, maraviroc has been introduced to phase II-III trials in HIV infection and AIDS, as well as to phase II trial in RA (176).

6. SUMMARY

In this review, we have discussed the potential role of chemokines and chemokine receptors in the pathogenesis of arthritis. Numerous CXC, as well as some CC and CX3C chemokines and their respective receptors have been implicated in leukocyte ingress into the inflamed synovium. Some chemokines and chemokine receptors are also involved in synovial angiogenesis. Anti-chemokine and anti-chemokine receptor targeting using either nonspecific compounds or specific inhibitors may control synovial inflammation.

Acknowledgments

This work was supported by NIH grants AR-048267 and AI-40987 (A.E.K.), the William D. Robinson, M.D. and Frederick G.L. Huetwell Endowed Professorship (A.E.K.), Funds from the Veterans’ Administration (A.E.K.); and grant No T048541 from the National Scientific Research Fund (OTKA) (Z.S.).

Abbreviations

AIA
adjuvant-induced arthritis
CIA
collagen-induced arthritis
DMARD
disease-modifying antirheumatic drugs
RA
rheumatoid arthritis

Footnotes

1Already targeted in animal models (A) or human (H) trials. See text for abbreviations

References

1. Koch AE. Review: angiogenesis: implications for rheumatoid arthritis. Arthritis Rheum. 1998;41:951–962. [PubMed]
2. Koch AE. Chemokines and their receptors in rheumatoid arthritis: future targets? Arthritis Rheum. 2005;52:710–721. [PubMed]
3. Paleolog EM, Fava RA. Angiogenesis in rheumatoid arthritis: implications for future therapeutic strategies. Springer Semin Immunopathol. 1998;20:73–94. [PubMed]
4. Rudolph EH, Woods JM. Chemokine expression and regulation of angiogenesis in rheumatoid arthritis. Curr PharmDes. 2005;11:613–631. [PubMed]
5. Szekanecz Z, Koch AE. Chemokines and angiogenesis. Curr Opin Rheumatol. 2001;13:202–208. [PubMed]
6. Szekanecz Z, Kim J, Koch AE. Chemokines and chemokine receptors in rheumatoid arthritis. Seminars in Immunology. 2002;399:1–7.
7. Szekanecz Z, Koch AE. Vascular endothelium and immune responses: implications for inflammation and angiogenesis. Rheum Dis Clin North Am. 2004;30:97–114. [PubMed]
8. Szekanecz Z, Gaspar L, Koch AE. Angiogenesis in rheumatoid arthritis. Front Biosci. 2005;10:1739–1753. [PubMed]
9. Szekanecz Z, Szucs G, Szanto S, Koch AE. Chemokines in rheumatic diseases. Curr Drug Targets. 2006;7:91–102. [PubMed]
10. Vergunst CE, Tak PP. Chemokines: their role in rheumatoid arthritis. Curr Rheumatol Rep. 2005;7:382–388. [PubMed]
11. Veale DJ, Fearon U. Inhibition of angiogenic pathways in rheumatoid arthritis: potential for therapeutic targeting. Best Pract Res Clin Rheumatol. 2006;20:941–947. [PubMed]
12. Milkiewicz M, Ispanovic E, Doyle JL, Haas TL. Regulators of angiogenesis and strategies for their therapeutic manipulation. Int J Biochem Cell Biol. 2006;38:333–357. [PubMed]
13. Bacon K, Baggiolini M, Broxmeyer H, Horuk R, Lindley I, Mantovani A, Maysushima K, Murphy P, Nomiyama H, Oppenheim J, Rot A, Schall T, Tsang M, Thorpe R, Van Damme J, Wadhwa M, Yoshie O, Zlotnik A, Zoon K. Chemokme/chemokine receptor nomenclature. J Interferon Cytokine Res. 2002;22:1067–1068. [PubMed]
14. Taub DD. C-C chemokines - an overview. 1996:27–54.
15. Walz A, Kunkel SL, Strieter RM. C-X-C chemokines - an overview. 1996:1–25.
16. Zlotnik A, Yoshie O. Chemokines: a new classification system and their role in immunity. Immunity. 2000;12:121–127. [PubMed]
17. Strieter RM, Polverini PJ, Kunkel SL, Arenberg DA, Burdick MD, Kasper J, Dzuiba J, Van Damme J, Walz A, Marriott D. The functional role of the ELR motif in CXC chemokine-mediated angiogenesis. J Biol Chem. 1995;270:27348–27357. [PubMed]
18. Deleuran B, Lemche P, Kristensen M, Chu CQ, Field M, Jensen J, Matsushima K, Stengaard-Pedersen K. Localisation of interleukin 8 in the synovial membrane, cartilage-pannus junction and chondrocytes in rheumatoid arthritis. Scand J Rheumatol. 1994;23:2–7. [PubMed]
19. Hosaka S, Akahoshi T, Wada C, Kondo H. Expression of the chemokine superfamily in rheumatoid arthritis. Clin Exp Immunol. 1994;97:451–457. [PubMed]
20. Koch AE, Kunkel SL, Burrows JC, Evanoff HL, Haines GK, Pope RM, Strieter RM. Synovial tissue macrophage as a source of the chemotactic cytokine IL-8. J Immunol. 1991;147:2187–2195. [PubMed]
21. Koch AE, Kunkel SL, Harlow LA, Mazarakis DD, Haines GK, Burdick MD, Pope RM, Walz A, Strieter RM. Epithelial neutrophil activating peptide-78: a novel chemotactic cytokine for neutrophils in arthritis. J Clin Invest. 1994;94:1012–1018. [PMC free article] [PubMed]
22. Koch AE, Kunkel SL, Shah MR, Hosaka S, Halloran MM, Haines GK, Burdick MD, Pope RM, Strieter RM. Growth-related gene product alpha. A chemotactic cytokine for neutrophils in rheumatoid arthritis. J Immunol. 1995;155:3660–3666. [PubMed]
23. Koch AE, Volin MV, Woods JM, Kunkel SL, Connors MA, Harlow LA, Woodruff DC, Burdick MD, Strieter RM. Regulation of angiogenesis by the C-X-C chemokines interleukin-8 and epithelial neutrophil activating peptide 78 in the rheumatoid joint. Arthritis Rheum. 2001;44:31–40. [PubMed]
24. Szekanecz Z, Koch AE. Macrophages and their products in rheumatoid arthritis. Curr Opin Rheumatol. 2007;19:289–295. [PubMed]
25. Konig A, Krenn V, Toksoy A, Gerhard N, Gillitzer R. Mig, GRO alpha and RANTES messenger RNA expression in lining layer, infiltrates and different leucocyte populations of synovial tissue from patients with rheumatoid arthritis, psoriatic arthritis and osteoarthritis. Virchows Arch. 2000;436:449–458. [PubMed]
26. Georganas C, Liu H, Perlman H, Hoffmann A, Thimmapaya B, Pope RM. Regulation of IL-6 and IL-8 expression in rheumatoid arthritis synovial fibroblasts: the dominant role for NF-kappa B but not C/EBP beta or c-Jun. J Immunol. 2000;165:7199–7206. [PubMed]
27. Patterson AM, Gardner L, Shaw J, David G, Loreau E, Aguilar L, Ashton BA, Middleton J. Induction of a CXCL8 binding site on endothelial syndecan-3 in rheumatoid synovium. Arthritis Rheum. 2005;52:2331–2342. [PubMed]
28. Chen Y, Davidson BL, Marks RM. Adenovirus-mediated transduction of the interleukin 8 gene into synoviocytes. Arthritis Rheum. 1994;37:S304.
29. Halloran MM, Woods JM, Strieter RM, Szekanecz Z, Volin MV, Hosaka S, Haines GK, III, Kunkel SL, Burdick MD, Walz A, Koch AE. The role of an epithelial neutrophil-activating peptide-78-like protein in rat adjuvant-induced arthritis. J Immunol. 1999;162:7492–7500. [PubMed]
30. Unemori EN, Amento EP, Bauer EA, Horuk R. Melanoma growth-stimulatory activity/GRO decreases collagen expression by human fibroblasts: Regulation by C-X-C but not C-C cytokines. J Biol Chem. 1993;268:1338–1342. [PubMed]
31. Castor CW, Smith EM, Hossler PA, Bignall MC, Aaron BP. Connective tissue activation. XXXV: Detection of connective tissue activating peptide-III isoforms in synovium from osteoarthritis and rheumatoid arthritis patients: patterns of interaction with other synovial cytokines in cell culture. Arthritis Rheum. 1992;35:783–793. [PubMed]
32. Castor CW, Andrews PC, Swartz RD, Ellis SG, Hossler PA, Clark MR, Matteson EL, Sachter EF. Connective tissue activation. XXXVI. The origin, variety, distribution, and biologic fate of connective tissue activating peptide-III isoforms: characteristics in patients with rheumatic, renal, and arterial disease. Arthritis Rheum. 1993;36:1142–1153. [PubMed]
33. Pierer M, Rethage J, Seibl R, Lauener R, Brentano F, Wagner U, Hantzschel H, Michel BA, Gay RE, Gay S, Kyburz D. Chemokine secretion of rheumatoid arthritis synovial fibroblasts stimulated by Toll-like receptor 2 ligands. J Immunol. 2004;172:1256–1265. [PubMed]
34. Blades MC, Ingegnoli F, Wheller SK, Manzo A, Wahid S, Panayi GS, Perretti M, Pitzalis C. Stromal cell-derived factor 1 (CXCL12) induces monocyte migration into human synovium transplanted onto SCID Mice. Arthritis Rheum. 2002;46:824–836. [PubMed]
35. Hanaoka R, Kasama T, Muramatsu M, Yajima N, Shiozawa F, Miwa Y, Negishi M, Ide H, Miyaoka H, Uchida H, Adachi M. A novel mechanism for the regulation of IFN-gamma inducible protein-10 expression in rheumatoid arthritis. Arthritis Res Ther. 2003;5:R74–R81. [PMC free article] [PubMed]
36. Patel DD, Zachariah JP, Whichard LP. CXCR.3 and CCR5 ligands in rheumatoid arthritis synovium. Clin Immunol. 2001;98:39–45. [PubMed]
37. Bradfield PF, Amft N, Vernon-Wilson E, Exley AE, Parsonage G, Rainger GE, Nash GB, Thomas AM, Simmons DL, Salmon M, Buckley CD. Rheumatoid fibroblast-like synoviocytes overexpress the chemokine stromal cell-derived factor 1 (CXCL12), which supports distinct patterns and rates of CD4+ and CD8+ T cell migration within synovial tissue. Arthritis Rheum. 2003;48:2472–2482. [PubMed]
38. Hansen IB, Ellingsen T, Hornung N, Poulsen JH, Lottenburger T, Stengaard-Pedersen K. Plasma level of CXC-chemokine CXCL12 is increased in rheumatoid arthritis and is independent of disease activity and methotrexate treatment. J Rheumatol. 2006;33:1754–1759. [PubMed]
39. Nanki T, Hayashida K, El Gabalawy HS, Suson S, Shi K, Girschick HJ, Yavuz S, Lipsky PE. Stromal cell-derived factor-1-CXC chemokine receptor 4 interactions play a central role in CD4+ T cell accumulation in rheumatoid arthritis synovium. J Immunol. 2000;165:6590–6598. [PubMed]
40. Buckley CD. Michael Mason prize essay 2003: Why do leucocytes accumulate within chronically inflamed joints? Rheumatology (Oxford) 2003;42:1433–1444. [PubMed]
41. Kim KW, Cho ML, Kim HR, Ju JH, Park MK, Oh HJ, Kim JS, Park SH, Lee SH, Kim HY. Up-regulation of stromal cell-derived factor 1 (CXCL12) production in rheumatoid synovial fibroblasts through interactions with T lymphocytes: role of interleukin-17 and CD40L-CD40 interaction. Arthritis Rheum. 2007;56:1076–1086. [PubMed]
42. Gronthos S, Zannettino AC. The role of the chemokine CXCL12 in osteoclastogenesis. Trends Endocrinol Metab. 2007;18:108–113. [PubMed]
43. Joven B, Gonzalez N, Aguilar F, Santiago B, Galindo M, Alcarni J, Pablos JL. Association between stromal cell-derived factor 1 chemokine gene variant and radiographic progression of rheumatoid arthritis. Arthritis Rheum. 2005;52:354–356. [PubMed]
44. Santiago B, Baleux F, Palao G, Gutierrez-Canas I, Ramirez JC, Arenzana-Seisdedos F, Pablos JL. CXCL12 is displayed by rheumatoid endothelial cells through its basic amino-terminal motif on heparan sulfate proteoglycans. Arthritis Res Ther. 2006;8:R43. [PMC free article] [PubMed]
45. De Vita S, Zaja F, Sacco S, De Candia A, Fanin R, Ferraccioli G. Efficacy of selective B cell blockade in the treatment of rheumatoid arthritis: evidence for a pathogenetic role of B cells. Arthritis Rheum. 2002;46:2029–2033. [PubMed]
46. Edwards JC, Cambridge G, Abrahams VM. Do self-perpetuating B lymphocytes drive human autoimmune disease? Immunology. 1999;97:188–196. [PubMed]
47. Silverman GJ, Carson DA. Roles of B cells in rheumatoid arthritis. Arthritis Res Ther. 2003;5(Suppl 4):S1–S6. [PMC free article] [PubMed]
48. Manzo A, Paoletti S, Carulli M, Blades MC, Barone F, Yanni G, Fitzgerald O, Bresnihan B, Caporali R, Montecucco C, Uguccioni M, Pitzalis C. Systematic microanatomical analysis of CXCL13 and CCL21 in situ production and progressive lymphoid organization in rheumatoid synovitis. Eur J Immunol. 2005;35:1347–1359. [PubMed]
49. Nanki T, Shimaoka T, Hayashida K, Taniguchi K, Yonehara S, Miyasaka N. Pathogenic role of the CXCL16-CXCR6 pathway in rheumatoid arthritis. Arthritis Rheum. 2005;52:3004–3014. [PubMed]
50. Ruth JH, Haas CS, Park CC, Amin MA, Martinez RJ, Haines GK, III, Shahrara S, Campbell PL, Koch AE. CXCL 16-mediated cell recruitment to rheumatoid arthritis synovial tissue and murine lymph nodes is dependent upon the MAPK pathway. Arthritis Rheum. 2006;54:765–778. [PMC free article] [PubMed]
51. d van V, van Lieshout AW, Toonen LW, Sloetjes AW, van den Berg WB, Figdor CG, Radstake TR, Adema GJ. Elevated CXCL16 expression by synovial macrophages recruits memory T cells into rheumatoid joints. Arthritis Rheum. 2005;52:1381–1391. [PubMed]
52. Koch AE, Kunkel SL, Harlow LA, Johnson B, Evanoff HL, Haines GK, Burdick MD, Pope RM, Strieter RM. Enhanced production of monocyte chemoattractant protein-1 in rheumatoid arthritis. J Clin Invest. 1992;90:772–779. [PMC free article] [PubMed]
53. Villiger PM, Terkeltaub R, Lotz M. Production of monocyte chemoattractant protein-1 by inflamed synovial tissue and cultured synoviocytes. J Immunol. 1992;149:722–727. [PubMed]
54. Volin MV, Shah MR, Tokuhira M, Haines GK, Woods JM, Koch AE. RANTES expression and contribution to monocyte chemotaxis in arthritis. Clin Immunol Immunopathol. 1998;89:44–53. [PubMed]
55. Rathanaswami P, Hachicha M, Sadick M, Schall TJ, McColl SR. Expression of the cytokine RANTES in human rheumatoid synovial fibroblasts: Differential regulation of RANTES and interleukin-8 genes by inflammatory cytokines. J Biol Chem. 1993;268:5834–5839. [PubMed]
56. Yoo JK, Kwon H, Khil LY, Zhang L, Jun HS, Yoon JW. IL-18 induces monocyte chemotactic protein-1 production in macrophages through the phosphatidylinositol 3-kinase/Akt and MEK/ERK1/2 pathways. J Immunol. 2005;175:8280–8286. [PubMed]
57. Safronova O, Nakahama K, Onodera M, Muneta T, Morita I. Effect of hypoxia on monocyte chemotactic protein-1 (MCP-1) gene expression induced by Interleukin-1 beta in human synovial fibroblasts. Inflamm Res. 2003;52:480–486. [PubMed]
58. Akahoshi T, Wada C, Endo H, Hirota K, Hosaka S, Takagishi K, Kondo H, Kashiwazaki S, Matsushima K. Expression of monocyte chemotactic and activating factor in rheumatoid arthritis: Regulation of its production in synovial cells by interleukin-1 and tumor necrosis factor. Arthritis Rheum. 1993;36:762–771. [PubMed]
59. Hounoki H, Sugiyama E, Mohamed SG, Shinoda K, Taki H, Abdel-Aziz HO, Maruyama M, Kobayashi M, Miyahara T. Activation of peroxisome proliferator-activated receptor gamma inhibits TNF-alpha-mediated osteoclast differentiation in human peripheral monocytes in part via suppression of monocyte chemoattractant protein-1 expression. Bone. 2008;42:765–774. [PubMed]
60. Koch AE, Kunkel SL, Harlow LA, Mazarakis DD, Haines GK, Burdick MD, Pope RM, Strieter RM. Macrophage inflammatory protein-1 alpha: A novel chemotactic cytokine for macrophages in rheumatoid arthritis. J Clin Invest. 1994;93:921–928. [PMC free article] [PubMed]
61. Wang CR, Liu MF. Regulation of CCR5 expression and MIP-1alpha production in CD4+ T cells from patients with rheumatoid arthritis. Clin Exp Immunol. 2003;132:371–378. [PubMed]
62. Wang CR, Guo HR, Liu MF. RANTES promoter polymorphism as a genetic risk factor for rheumatoid arthritis in the Chinese. Clin Exp Rheumatol. 2005;23:379–384. [PubMed]
63. Matsui T, Akahoshi T, Namai R, Hashimoto A, Kurihara Y, Rana M, Nishimura A, Endo H, Kitasato H, Kawai S, Takagishi K, Kondo H. Selective recruitment of CCR6-expressing cells by increased production of MIP-3 alpha in rheumatoid arthritis. Clin Exp Immunol. 2001;125:155–161. [PubMed]
64. Chabaud M, Page G, Miossec P. Enhancing effect of IL-1, IL-17, and TNF-alpha on macrophage inflammatory protein-3alpha production in rheumatoid arthritis: regulation by soluble receptors and Th2 cytokines. J Immunol. 2001;167:6015–6020. [PubMed]
65. Ruth JH, Morel JCM, Park CC, Koch AE. MIP-3a expression in the rheumatoid joint. Arthritis Rheum. 2000;43:S78.
66. Schlenk J, Lorenz HM, Haas JP, Herrmann M, Hohenberger G, Kalden JR, Rollinghoff M, Beuscher HU. Extravasation into synovial tissue induces CCL20 mRNA expression in polymorphonuclear neutrophils of patients with rheumatoid arthritis. J Rheumatol. 2005;32:2291–2298. [PubMed]
67. Hirota K, Yoshitomi H, Hashimoto M, Maeda S, Teradaira S, Sugimoto N, Yamaguchi T, Nomura T, Ito H, Nakamura T, Sakaguchi N, Sakaguchi S. Preferential recruitment of CCR6-expressing Th17 cells to inflamed joints via CCL20 in rheumatoid arthritis and its animal model. J Exp Med. 2007;204:2803–2812. [PMC free article] [PubMed]
68. Lisignoli G, Piacentini A, Cristino S, Grassi F, Cavallo C, Cattini L, Tonnarelli B, Manferdini C, Facchini A. CCL20 chemokine induces both osteoblast proliferation and osteoclast differentiation: Increased levels of CCL20 are expressed in subchondral bone tissue of rheumatoid arthritis patients. J Cell Physiol. 2007;210:798–806. [PubMed]
69. van Lieshout AW, Fransen J, Flendrie M, Eijsbouts AM, van den Hoogen FH, van Riel PL, Radstake TR. Circulating levels of the chemokine CCL18 but not CXCL16 are elevated and correlate with disease activity in rheumatoid arthritis. Ann Rheum Dis. 2007;66:1334–1338. [PMC free article] [PubMed]
70. Auer J, Blass M, Schulze-Koops H, Russwurm S, Nagel T, Kalden JR, Rollinghoff M, Beuscher HU. Expression and regulation of CCL18 in synovial fluid neutrophils of patients with rheumatoid arthritis. Arthritis Res Ther. 2007;9:R94. [PMC free article] [PubMed]
71. Iwamoto T, Okamoto H, Kobayashi S, Ikari K, Toyama Y, Tomatsu T, Kamatani N, Momohara S. A role of monocyte chemoattractant protein-4 (MCP-4)/CCL13 from chondrocytes in rheumatoid arthritis. FEBS J. 2007;274:4904–4912. [PubMed]
72. Manzo A, Bugatti S, Caporali R, Prevo R, Jackson DG, Uguccioni M, Buckley CD, Montecucco C, Pitzalis C. CCL21 expression pattern of human secondary lymphoid organ stroma is conserved in inflammatory lesions with lymphoid neogenesis. Am J Pathol. 2007;171:1549–1562. [PubMed]
73. Momohara S, Okamoto H, Iwamoto T, Mizumura T, Ikari K, Kawaguchi Y, Takeuchi M, Kamatani N, Tomatsu T. High CCL18/PARC expression in articular cartilage and synovial tissue of patients with rheumatoid arthritis. J Rheumatol. 2007;34:266–271. [PubMed]
74. Okamoto H, Koizumi K, Yamanaka H, Saito T, Kamatani N. A role for TARC/CCL17, a CC chemokine, in systemic lupus erythematosus. J Rheumatol. 2003;30:2369–2373. [PubMed]
75. van Lieshout AW, d van V, le Blanc LM, Roelofs MF, Schreurs BW, van Riel PL, Adema GJ, Radstake TR. Novel insights in the regulation of CCL18 secretion by monocytes and dendritic cells via cytokines, toll-like receptors and rheumatoid synovial fluid. BMC Immunol. 2006;7:23. [PMC free article] [PubMed]
76. Haringman JJ, Smeets TJ, Reinders-Blankert P, Tak PP. Chemokine and chemokine receptor expression in paired peripheral blood mononuclear cells and synovial tissue of patients with rheumatoid arthritis, osteoarthritis, and reactive arthritis. Ann Rheum Dis. 2006;65:294–300. [PMC free article] [PubMed]
77. Li T, Zhong J, Chen Y, Qiu X, Zhang T, Ma D, Han W. Expression of chemokine-like factor 1 is upregulated during T lymphocyte activation. Life Sci. 2006;79:519–524. [PubMed]
78. Blaschke S, Middel P, Dorner BG, Blaschke V, Hummel KM, Kroczek RA, Reich K, Benoehr P, Koziolek M, Muller GA. Expression of activation-induced, T cell-derived, and chemokine-related cytokine/lymphotactin and its functional role in rheumatoid arthritis. Arthritis Rheum. 2003;48:1858–1872. [PubMed]
79. Borthwick NJ, Akbar AN, MacCormac LP, Lowdell M, Craigen JL, Hassan I, Grundy JE, Salmon M, Yong KL. Selective migration of highly differentiated primed T cells, defined by low expression of CD45RB, across human umbilical vein endothelial cells: effects of viral infection on transmigration. Immunology. 1997;90:272–280. [PubMed]
80. Bazan JF, Bacon KB, Hardiman G, Wang W, Soo K, Rossi D, Greaves DR, Zlotnik A, Schall TJ. A new class of membrane-bound chemokine with a CX3C motif. Nature. 1997;385:640–644. [PubMed]
81. Loetscher P, Uguccioni M, Bordoli L, Baggiolini M, Moser B, Chizzolini C, Dayer JM. CCR5 is characteristic of Th1 lymphocytes. Nature. 1998;391:344–345. [PubMed]
82. Ruth JH, Volin MV, Haines GK, III, Woodruff DC, Katschke KJ, Jr, Woods JM, Park CC, Morel JC, Koch AE. Fractalkine, a novel chemokine in rheumatoid arthritis and in rat adjuvant-induced arthritis. Arthritis Rheum. 2001;44:1568–1581. [PubMed]
83. Sawai H, Park YW, Roberson J, Imai T, Goronzy JJ, Weyand CM. T cell costimulation by fractalkine-expressing synoviocytes in rheumatoid arthritis. Arthritis Rheum. 2005;52:1392–1401. [PubMed]
84. Sawai H, Park YW, He X, Goronzy JJ, Weyand CM. Fractalkine mediates T cell-dependent proliferation of synovial fibroblasts in rheumatoid arthritis. Arthritis Rheum. 2007;56:3215–3225. [PubMed]
85. Volin MV, Huynh N, Klosowska K, Chong KK, Woods JM. Fractalkine is a novel chemoattractant for rheumatoid arthritis fibroblast-like synoviocyte signaling through MAP kinases and Akt. Arthritis Rheum. 2007;56:2512–2522. [PubMed]
86. Matsunawa M, Isozaki T, Odai T, Yajima N, Takeuchi HT, Negishi M, Ide H, Adachi M, Kasama T. Increased serum levels of soluble fractalkine (CX3CL1) correlate with disease activity in rheumatoid vasculitis. Arthritis Rheum. 2006;54:3408–3416. [PubMed]
87. McDermott DH, Fong AM, Yang Q, Sechler JM, Cupples LA, Merrell MN, Wilson PW, D’Agostino RB, O’Donnell CJ, Patel DD, Murphy PM. Chemokine receptor mutant CX3CR1–M280 has impaired adhesive function and correlates with protection from cardiovascular disease in humans. J Clin Invest. 2003;111:1241–1250. [PMC free article] [PubMed]
88. Pingiotti E, Cipriani P, Marrelli A, Liakouli V, Fratini S, Penco M, Giacomelli R. Surface expression of fractalkine receptor (CX3CR1) on CD4+/CD28 T cells in RA patients and correlation with atherosclerotic damage. Ann NY Acad Sci. 2007;1107:32–41. [PubMed]
89. Volin MV, Woods JM, Amin MA, Connors MA, Harlow LA, Koch AE. Fractalkine: a novel angiogenic chemokine in rheumatoid arthritis. Am J Pathol. 2001;159:1521–1530. [PubMed]
90. Garcia-Lopez MA, Sanchez-Madrid F, Rodriguez-Frade JM, Mellado M, Acevedo A, Garcia MI, Albar JP, Martinez C, Marazuela M. CXCR3 chemokine receptor distribution in normal and inflamed tissues: expression on activated lymphocytes, endothelial cells, and dendritic cells. Lab Invest. 2001;81:409–418. [PubMed]
91. Qin S, Rottman JB, Myers P, Kassam N, Weinblatt M, Loetscher M, Koch AE, Moser B, Mackay CR. The chemokine receptors CXCR3 and CCR5 mark subsets of T cells associated with certain inflammatory reactions. J Clin Invest. 1998;101:746–754. [PMC free article] [PubMed]
92. Wedderburn LR, Robinson N, Patel A, Varsani H, Woo P. Selective recruitment of polarized T cells expressing CCR5 and CXCR3 to the inflamed joints of children with juvenile idiopathic arthritis. Arthritis Rheum. 2000;43:765–774. [PubMed]
93. Schmutz C, Hulme A, Burman A, Salmon M, Ashton B, Buckley C, Middleton J. Chemokine receptors in the rheumatoid synovium: upregulation of CXCR5. Arthritis Res Ther. 2005;7:R217–R229. [PMC free article] [PubMed]
94. Ruth JH, Rottman JB, Katschke KJ, Jr, Qin S, Wu L, LaRosa G, Ponath P, Pope RM, Koch AE. Selective lymphocyte chemokine receptor expression in the rheumatoid joint. Arthritis Rheum. 2001;44:2750–2760. [PubMed]
95. Wengner AM, Hopken UE, Petrow PK, Hartmann S, Schurigt U, Brauer R, Lipp M. CXCR5 and CCR7 dependent lymphoid neogenesis in a murine model of chronic antigen-induced arthritis. Arthritis Rheum. 2007;56:3271–3283. [PubMed]
96. Moser B, Loetscher P. Lymphocyte traffic control by chemokines. Nat Immunol. 2001;2:123–128. [PubMed]
97. Katschke KJ, Jr, Rottman JB, Ruth JH, Qin S, Wu L, LaRosa G, Ponath P, Park CC, Pope RM, Koch AE. Differential expression of chemokine receptors on peripheral blood, synovial fluid, and synovial tissue monocytes/macrophages in rheumatoid arthritis. Arthritis Rheum. 2001;44:1022–1032. [PubMed]
98. Borzi RM, Mazzetti I, Cattini L, Uguccioni M, Baggiolini M, Facchini A. Human chondrocytes express functional chemokine receptors and release matrix-degrading enzymes in response to C-X-C and C-C chemokines. Arthritis Rheum. 2000;43:1734–1741. [PubMed]
99. Prahalad S. Negative association between the chemokine receptor CCR5-Delta32 polymorphism and rheumatoid arthritis: a meta-analysis. Genes Immun. 2006;7:264–268. [PMC free article] [PubMed]
100. Kohem CL, Brenol JC, Xavier RM, Bredemeier M, Brenol CV, Dedavid e Silva TL, de Castilhos MA, Canedo AD, Neves AG, Chies JA. The chemokine receptor CCR5 genetic polymorphism and expression in rheumatoid arthritis patients. Scand J Rheumatol. 2007;36:359–364. [PubMed]
101. Lindner E, Nordang GB, Melum E, Flato B, Selvaag AM, Thorsby E, Kvien TK, Forre OT, Lie BA. Lack of association between the chemokine receptor 5 polymorphism CCR5delta32 in rheumatoid arthritis and juvenile idiopathic arthritis. BMC Med Genet. 2007;8:33. [PMC free article] [PubMed]
102. Galligan CL, Matsuyama W, Matsukawa A, Mizuta H, Hodge DR, Howard OM, Yoshimura T. Up-regulated expression and activation of the orphan chemokine receptor, CCRL2, in rheumatoid arthritis. Arthritis Rheum. 2004;50:1806–1814. [PubMed]
103. Pablos JL, Santiago B, Galindo M, Torres C, Brehmer MT, Blanco FJ, Garcia-Lazaro FJ. Synoviocyte-derived CXCL12 is displayed on endothelium and induces angiogenesis in rheumatoid arthritis. J Immunol. 2003;170:2147–2152. [PubMed]
104. Wooley PH, Schaefer C, Whalen JD, Dutcher JA, Counts DF. A peptide sequence from platelet factor 4 (CT-112) is effective in the treatment of type II collagen induced arthritis in mice. J Rheumatol. 1997;24:890–898. [PubMed]
105. Norii M, Yamamura M, Iwahashi M, Ueno A, Yamana J, Makino H. Selective recruitment of CXCR3+ and CCR5+ CCR4+ T cells into synovial tissue in patients with rheumatoid arthritis. Acta Med Okayama. 2006;60:149–157. [PubMed]
106. Caunt M, Hu L, Tang T, Brooks PC, Ibrahim S, Karpatkin S. Growth-regulated oncogene is pivotal in thrombin-induced angiogenesis. Cancer Res. 2006;66:4125–4132. [PubMed]
107. Liang Z, Brooks J, Willard M, Liang K, Yoon Y, Kang S, Shim H. CXCR4/CXCL12 axis promotes VEGF-mediated tumor angiogenesis through Akt signaling pathway. Biochem Biophys Res Commun. 2007;359:716–722. [PMC free article] [PubMed]
108. Petit I, Jin D, Rafii S. The SDF-1-CXCR4 signaling pathway: a molecular hub modulating neo-angiogenesis. Trends Immunol. 2007;28:299–307. [PMC free article] [PubMed]
109. Calatozzolo C, Maderna E, Pollo B, Gelati M, Marras C, Silvani A, Croci D, Boiardi A, Salmaggi A. Prognostic value of CXCL12 expression in 40 low-grade oligodendrogliomas and oligoastrocytomas. Cancer Biol Ther. 2006;5:827–832. [PubMed]
110. Bodnar RJ, Yates CC, Wells A. IP-10 blocks vascular endothelial growth factor-induced endothelial cell motility and tube formation via inhibition of calpain. Circ Res. 2006;98:617–625. [PMC free article] [PubMed]
111. Boulday G, Haskova Z, Reinders ME, Pal S, Briscoe DM. Vascular endothelial growth factor-induced signaling pathways in endothelial cells that mediate overexpression of the chemokine IFN-gamma-inducible protein of 10 kDa in vitro and in vivo. J Immunol. 2006;176:3098–3107. [PubMed]
112. Maurer AM, Zhou B, Han ZC. Roles of platelet factor 4 in hematopoiesis and angiogenesis. Growth Factors. 2006;24:242–252. [PubMed]
113. Salcedo R, Ponce ML, Young HA, Wasserman K, Ward JM, Kleinman HK, Oppenheim JJ, Murphy WJ. Human endothelial cells express CCR2 and respond to MCP-1: direct role of MCP-1 in angiogenesis and tumor progression. Blood. 2000;96:34–40. [PubMed]
114. Stamatovic SM, Keep RF, Mostarica-Stojkovic M, Andjelkovic AV. CCL2 regulates angiogenesis via activation of Ets-1 transcription factor. J Immunol. 2006;177:2651–2661. [PubMed]
115. Son KN, Hwang J, Kwon BS, Kim J. Human CC chemokine CCL23 enhances expression of matrix metalloproteinase-2 and invasion of vascular endothelial cells. Biochem Biophys Res Commun. 2006;340:498–504. [PubMed]
116. Vicari AP, Ait-Yahia S, Chemin K, Mueller A, Zlotnik A, Caux C. Antitumor effects of the mouse chemokine 6Ckine/SLC through angiostatic and immunological mechanisms. J Immunol. 2000;165:1992–2000. [PubMed]
117. Buckley CD, Amft N, Bradfield PF, Pilling D, Ross E, Arenzana-Seisdedos F, Amara A, Curnow SJ, Lord JM, Scheel-Toellner D, Salmon M. Persistent induction of the chemokine receptor CXCR4 by TGF-beta 1 on synovial T cells contributes to their accumulation within the rheumatoid synovium. J Immunol. 2000;165:3423–3429. [PubMed]
118. Zagzag D, Lukyanov Y, Lan L, Ali MA, Esencay M, Mendez O, Yee H, Voura EB, Newcomb EW. Hypoxia-inducible factor 1 and VEGF upregulate CXCR4 in glioblastoma: implications for angiogenesis and glioma cell invasion. Lab Invest. 2006;86:1221–1232. [PubMed]
119. Burns JM, Summers BC, Wang Y, Melikian A, Berahovich R, Miao Z, Penfold ME, Sunshine MJ, Littman DR, Kuo CJ, Wei K, McMaster BE, Wright K, Howard MC, Schall TJ. A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development. J Exp Med. 2006;203:2201–2213. [PMC free article] [PubMed]
120. Ochoa O, Sun D, Reyes-Reyna SM, Waite LL, Michalek JE, McManus LM, Shireman PK. Delayed angiogenesis and VEGF production in CCR2−/− mice during impaired skeletal muscle regeneration. Am J Physiol Regul Integr Comp Physiol. 2007;293:R651–R661. [PubMed]
121. Lesnik P, Haskell CA, Charo IF. Decreased atherosclerosis in CX3CR1−/− mice reveals a role for fractalkine in atherogenesis. J Clin Invest. 2003;111:333–340. [PMC free article] [PubMed]
122. Szekanecz Z, Halloran MM, Volin MV, Woods JM, Strieter RM, Kenneth HG, III, Kunkel SL, Burdick MD, Koch AE. Temporal expression of inflammatory cytokines and chemokines in rat adjuvant-induced arthritis. Arthritis Rheum. 2000;43:1266–1277. [PubMed]
123. Haas CS, Martinez RJ, Attia N, Haines GK, III, Campbell PL, Koch AE. Chemokine receptor expression in rat adjuvant-induced arthritis. Arthritis Rheum. 2005;52:3718–3730. [PubMed]
124. Feldmann M, Brennan FM, Maini RN. Role of cytokines in rheumatoid arthritis. Annu Rev Immunol. 1996;14:397–440. [PubMed]
125. Szekanecz Z, Koch AE, Kunkel SL, Strieter RM. Cytokines in rheumatoid arthritis: Potential targets for pharmacological intervention. Drugs Aging. 1998;12:377–390. [PubMed]
126. Fahey TJ, III, Tracey KJ, Tekamp-Olson P, Cousens LS, Jones WG, Shires GT, Cerami A, Sherry B. Macrophage inflammatory protein 1 modulates macrophage function. J Immunol. 1992;148:2764–2769. [PubMed]
127. Tak PP. Chemokine inhibition in inflammatory arthritis. Best Pract Res Clin Rheumatol. 2006;20:929–939. [PubMed]
128. Lopez-Armada MJ, Sanchez-Pernaute O, Largo R, Diez-Ortego I, Palacios I, Egido J, Herrero-Beaumont G. Modulation of cell recruitment by anti-inflammatory agents in antigen-induced arthritis. Ann Rheum Dis. 2002;61:1027–1030. [PMC free article] [PubMed]
129. Loetscher P, Dewald B, Baggiolini M, Seitz M. Monocyte chemoattractant protein 1 and interleukin 8 production by rheumatoid synoviocytes: Effects of anti-rheumatic drugs. Cytokine. 1994;6:162–170. [PubMed]
130. Volin MV, Campbell PL, Connors MA, Woodruff DC, Koch AE. The effect of sulfasalazine on rheumatoid arthritic synovial tissue chemokine production. Exp Mol Pathol. 2002;73:84–92. [PubMed]
131. Volin MV, Harlow LA, Woods JM, Campbell PL, Amin MA, Tokuhira M, Koch AE. Treatment with sulfasalazine or sulfapyridine, but not 5-aminosalicyclic acid, inhibits basic fibroblast growth factor-induced endothelial cell chemotaxis. Arthritis Rheum. 1999;42:1927–1935. [PubMed]
132. Ho CY, Wong CK, Li EK, Tam LS, Lam CW. Suppressive effect of combination treatment of leflunomide and methotrexate on chemokine expression in patients with rheumatoid arthritis. Clin Exp Immunol. 2003;133:132–138. [PubMed]
133. Ellingsen T, Hornung N, Moller BK, Poulsen JH, Stengaard-Pedersen K. Differential effect of methotrexate on the increased CCR2 density on circulating CD4 T lymphocytes and monocytes in active chronic rheumatoid arthritis, with a down regulation only on monocytes in responders. Ann Rheum Dis. 2007;66:151–157. [PMC free article] [PubMed]
134. Kageyama Y, Torikai E, Nagano A. Anti-tumor necrosis factor-alpha antibody treatment reduces serum CXCL16 levels in patients with rheumatoid arthritis. Rheumatol Int. 2006;27:467–472. [PubMed]
135. Klimiuk PA, Sierakowski S, Domyslawska I, Chwiecko J. Regulation of serum chemokines following infliximab therapy in patients with rheumatoid arthritis. Clin Exp Rheumatol. 2006;24:529–533. [PubMed]
136. Taylor PC, Peters AM, Paleolog E, Chapman PT, Elliott MJ, McCloskey R, Feldmann M, Maini RN. Reduction of chemokine levels and leukocyte traffic to joints by tumor necrosis factor alpha blockade in patients with rheumatoid arthritis. Arthritis Rheum. 2000;43:38–47. [PubMed]
137. Torikai E, Kageyama Y, Suzuki M, Ichikawa T, Nagano A. The effect of infliximab on chemokines in patients with rheumatoid arthritis. Clin Rheumatol. 2007;26:1088–1093. [PubMed]
138. Nissinen R, Leirisalo-Repo M, Peltomaa R, Palosuo T, Vaarala O. Cytokine and chemokine receptor profile of peripheral blood mononuclear cells during treatment with infliximab in patients with active rheumatoid arthritis. Ann Rheum Dis. 2004;63:681–687. [PMC free article] [PubMed]
139. Aeberli D, Seitz M, Juni P, Villiger PM. Increase of peripheral CXCR3 positive T lymphocytes upon treatment of RA patients with TNF-alpha inhibitors. Rheumatology (Oxford) 2005;44:172–175. [PubMed]
140. Newton SM, Mackie SL, Martineau AR, Wilkinson KA, Kampmann B, Fisher C, Dutta S, Levin M, Wilkinson RJ, Pasvol G. Reduction of chemokine secretion in response to mycobacteria in infliximab-treated patients. Clin Vaccine Immunol. 2008;15:506–512. [PMC free article] [PubMed]
141. Sato M, Miyazaki T, Nagaya T, Murata Y, Ida N, Maeda K, Seo H. Antioxidants inhibit tumor necrosis factor-alpha mediated stimulation of interleukin-8, monocyte chemoattractant protein-1, and collagenase expression in cultured human synovial cells. J Rheumatol. 1996;23:432–438. [PubMed]
142. Yokota K, Miyazaki T, Hirano M, Akiyama Y, Mimura T. Simvastatin inhibits production of mterleukm 6 (IL-6) and IL-8 and cell proliferation induced by tumor necrosis factor-alpha in fibroblast-like synoviocytes from patients with rheumatoid arthritis. J Rheumatol. 2006;33:463–471. [PubMed]
143. Wang Y, Wei D, Lai Z, Le Y. Triptolide inhibits CC chemokines expressed in rat adjuvant-induced arthritis. Int Immunopharmacol. 2006;6:1825–1832. [PubMed]
144. Ahmed S, Pakozdi A, Koch AE. Regulation of interleukin-1beta-induced chemokine production and matrix metalloproteinase 2 activation by epigallocatechin-3-gallate in rheumatoid arthritis synovial fibroblasts. Arthritis Rheum. 2006;54:2393–2401. [PubMed]
145. Ospelt C, Kurowska-Stolarska M, Neidhart M, Michel BA, Gay RE, Laufer S, Gay S. The dual inhibitor of lipoxygenase and cyclooxygenase ML3000 decreases the expression of CXCR3 ligands. Ann Rheum Dis. 2008;67:524–529. [PubMed]
146. Akahoshi T, Endo H, Kondo H, Kashiwazaki S, Kasahara T, Mukaida N, Harada A, Matsushima K. Essential involvement of interleukin-8 in neutrophil recruitment in rabbits with acute experimental arthritis induced by lipopolysaccharide and interleukin-1. Lymphokine Cytokine Res. 1994;13:113–116. [PubMed]
147. Kasama T, Strieter RM, Lukacs NW, Lincoln PM, Burdick MD, Kunkel SL. Interleukin-10 expression and chemokine regulation during the evolution of murine type II collagen-induced arthritis. J Clin Invest. 1995;95:2868–2876. [PMC free article] [PubMed]
148. Ogata H, Takeya M, Yoshimura T, Takagi K, Takahashi K. The role of monocyte chemoattractant protein-1 (MCP-1) in the pathogenesis of collagen-induced arthritis in rats. J Pathol. 1997;182:106–114. [PubMed]
149. Schrier DJ, Schimmer RC, Flory CM, Tung DK, Ward PA. Role of chemokines and cytokines in a reactivation model of arthritis in rats induced by injection with streptococcal cell walls. J Leukoc Biol. 1998;63:359–363. [PubMed]
150. Shahrara S, Proudfoot AE, Park CC, Volin MV, Haines GK, Woods JM, Aikens CH, Handel TM, Pope RM. Inhibition of monocyte chemoattractant protein-1 ameliorates rat adjuvant-induced arthritis. J Immunol. 2008;180:3447–3456. [PubMed]
151. Gong JH, Ratkay LG, Waterfield JD, Clark-Lewis I. An antagonist of monocyte chemoattractant protein 1 (MCP-1) inhibits arthritis in the MRL-1pr mouse model. J Exp Med. 1997;186:131–137. [PMC free article] [PubMed]
152. Barnes DA, Tse J, Kaufhold M, Owen M, Hesselgesser J, Strieter R, Horuk R, Perez HD. Polyclonal antibody directed against human RANTES ameliorates disease in the Lewis rat adjuvant-induced arthritis model. J Clin Invest. 1998;101:2910–2919. [PMC free article] [PubMed]
153. Inoue T, Yamashita M, Higaki M. The new antirheumatic drug KE-298 suppresses monocyte chemoattractant protein (MCP)-1 and RANTES production in rats with adjuvant-induced arthritis and in IL-1beta-stimulated synoviocytes of patients with rheumatoid arthritis. Rheumatol Int. 2001;20:149–153. [PubMed]
154. Nanki T, Urasaki Y, Imai T, Nishimura M, Muramoto K, Kubota T, Miyasaka N. Inhibition of fractalkine ameliorates murine collagen-induced arthritis. J Immunol. 2004;173:7010–7016. [PubMed]
155. Gong JH, Yan R, Waterfield JD, Clark-Lewis I. Post-onset inhibition of murine arthritis using combined chemokine antagonist therapy. Rheumatology (Oxford) 2004;43:39–42. [PubMed]
156. Matsukawa A, Yoshimura T, Fujiwara K, Maeda T, Ohkawara S, Yoshinaga M. Involvement of growth-related protein in lipopolysaccharide-induced rabbit arthritis: cooperation between growth-related protein and IL-8, and interrelated regulation among TNFalpha, IL-1, IL-1 receptor antagonist, IL-8, and growth-related protein. Lab Invest. 1999;79:591–600. [PubMed]
157. Podolin PL, Bolognese BJ, Foley JJ, Schmidt DB, Buckley PT, Widdowson KL, Jin Q, White JR, Lee JM, Goodman RB, Hagen TR, Kajikawa O, Marshall LA, Hay DW, Sarau HM. A potent and selective nonpeptide antagonist of CXCR2 inhibits acute and chronic models of arthritis in the rabbit. J Immunol. 2002;169:6435–6444. [PubMed]
158. Barsante MM, Cunha TM, Allegretti M, Cattani F, Policani F, Bizzarri C, Tafuri WL, Poole S, Cunha FQ, Bertini R, Teixeira MM. Blockade of the chemokine receptor CXCR2 ameliorates adjuvant-induced arthritis in rats. Br J Pharmacol. 2008;153:992–1002. [PMC free article] [PubMed]
159. Cunha TM, Barsante MM, Guerrero AT, Verri WA, Jr, Ferreira SH, Coelho FM, Bertini R, Di Giacinto C, Allegretti M, Cunha FQ, Teixeira MM. Treatment with DF 2162, a non-competitive allosteric inhibitor of CXCR1/2, diminishes neutrophil influx and inflammatory hypernociception in mice. Br J Pharmacol. 2008;154:460–470. [PMC free article] [PubMed]
160. Mohan K, Issekutz TB. Blockade of chemokine receptor CXCR3 inhibits T cell recruitment to inflamed joints and decreases the severity of adjuvant arthritis. J Immunol. 2007;179:8463–8469. [PubMed]
161. Khan A, Greenman J, Archibald SJ. Small molecule CXCR4 chemokine receptor antagonists: developing drug candidates. Curr Med Chem. 2007;14:2257–2277. [PubMed]
162. Hatse S, Princen K, Bridger G, De Clercq E, Schols D. Chemokine receptor inhibition by AMD3100 is strictly confined to CXCR4. FEBS Lett. 2002;527:255–262. [PubMed]
163. Tamamura H, Fujii N. The therapeutic potential of CXCR4 antagonists in the treatment of HIV infection, cancer metastasis and rheumatoid arthritis. Expert Opin Ther Targets. 2005;9:1267–1282. [PubMed]
164. Amat M, Benjamim CF, Williams LM, Prats N, Terricabras E, Beleta J, Kunkel SL, Godessart N. Pharmacological blockade of CCR1 ameliorates murine arthritis and alters cytokine networks in vivo. Br J Pharmacol. 2006;149:666–675. [PMC free article] [PubMed]
165. Gladue RP, Tylaska LA, Brissette WH, Lira PD, Kath JC, Poss CS, Brown MF, Paradis TJ, Conklyn MJ, Ogborne KT, McGlynn MA, Lillie BM, DiRico AP, Mairs EN, McElroy EB, Martin WH, Stock IA, Shepard RM, Showell HJ, Neote K. CP-481, 715, a potent and selective CCR1 antagonist with potential therapeutic implications for inflammatory diseases. J Biol Chem. 2003;278:40473–40480. [PubMed]
166. Haringman JJ, Kraan MC, Smeets TJ, Zwinderman KH, Tak PP. Chernokine blockade and chronic inflammatory disease: proof of concept in patients with rheumatoid arthritis. Ann Rheum Dis. 2003;62:715–721. [PMC free article] [PubMed]
167. Pease JE, Horuk R. CCR1 antagonists in clinical development. Expert Opin Investig Drugs. 2005;14:785–796. [PubMed]
168. Quinones MP, Estrada CA, Kalkonde Y, Ahuja SK, Kuziel WA, Mack M, Ahuja SS. The complex role of the chemokine receptor CCR2 in collagen- induced arthritis: implications for therapeutic targeting of CCR2 in rheumatoid arthritis. J Mol Med. 2005;83:672–681. [PubMed]
169. Quinones MP, Jimenez F, Martinez H, Estrada CA, Willmon O, Dudley M, Kuziel WA, Melby PC, Reddick RL, Ahuja SK, Ahuja SS. CC chemokine receptor (CCR)-2 prevents arthritis development following infection by Mycobacterium avium. J Mol Med. 2006;84:503–512. [PubMed]
170. Plater-Zyberk C, Hoogewerf AJ, Proudfoot AE, Power CA, Wells TN. Effect of a CC chemokine receptor antagonist on collagen induced arthritis in DBA/1 mice. Immunol Lett. 1997;57:117–120. [PubMed]
171. Shahrara S, Proudfoot AE, Woods JM, Ruth JH, Amin MA, Park CC, Haas CS, Pope RM, Haines GK, Zha YY, Koch AE. Amelioration of rat adjuvant-induced arthritis by Met-RANTES. Arthritis Rheum. 2005;52:1907–1919. [PMC free article] [PubMed]
172. Bruhl H, Cihak J, Plachy J, Kunz-Schughart L, Niedermeier M, Denzel A, Rodriguez GM, Talke Y, Luckow B, Stangassinger M, Mack M. Targeting of Gr-1+, CCR2+ monocytes in collagen-induced arthritis. Arthritis Rheum. 2007;56:2975–2985. [PubMed]
173. Bursill CA, Cai S, Channon KM, Greaves DR. Adenoviral-mediated delivery of a viral chemokine binding protein blocks CC-chemokine activity in vitro and in vivo. Immunobiology. 2003;207:187–196. [PubMed]
174. Haringman JJ, Gerlag DM, Smeets TJ, Baeten D, van den BF, Bresnihan B, Breedveld FC, Dinant HJ, Legay F, Gram H, Loetscher P, Schmouder R, Woodworth T, Tak PP. A randomized controlled trial with an anti-CCL2 (anti-monocyte chemotactic protein 1) monoclonal antibody in patients with rheumatoid arthritis. Arthritis Rheum. 2006;54:2387–2392. [PubMed]
175. Clucas AT, Shah A, Zhang YD, Chow VF, Gladue RP. Phase I evaluation of the safety, pharmacokinetics and pharmacodynamics of CP-481, 715. Clin Pharmacokinet. 2007;46:757–766. [PubMed]
176. Meanwell NA, Kadow JF. Maraviroc, a chemokine CCR5 receptor antagonist for the treatment of HIV infection and AIDS. Curr Opin Investig Drugs. 2007;8:669–681. [PubMed]