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.

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 (1-10). 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 (1-11). Thus, non-specific or specific blockade of chemokines may attenuate synovitis (1-12).

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 (2,5,6,13-16). 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).

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 (18-23). Synovial macrophages are major producers of IL-8/CXCL8, ENA-78/CXC5 and gro-alpha/CXCL1 (19-22,24), however, synovial lining cells, fibroblasts and endothelial cells may also release these chemokines (19-22,24,25). 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 chemotactic 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 (2,17,34-36). These chemokines have been detected in the sera. Synovial macrophages and fibroblasts release these chemokines (34-36). 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 (37-39). 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 (39,42-44).

The crucial role of B cells in the pathogenesis of RA has been acknowledged in recent years (45-47). Among homeostatic chemokines involved in B cell migration and lymphoid tissue organization, B-cell activating chemokine-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 (6,52-54). All these chemokines have been detected in RA sera and synovia (19,35,52-54). 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 (63-66). 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 (73-75).

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 (80-83). 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/CX₃CL1 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/CX₃CL1 has been associated with disease activity in rheumatoid vasculitis (86), as well as with accelerated atherosclerosis and increased cardiovascular morbidity in RA (87-89).

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 (87-89) (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 (5,15,17,110-112). 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).

Fractalkine/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 CHEMOKINES AND CHEMOKINE RECEPTORS

Chemokines and chemokine receptors may be targeted by non-specific, as well as by chemokine-specific 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 biologics 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 and MCP-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 (51,134-137). 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-lpr 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 fractalkine/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-groα/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 IFN-gamma-deficient mice (162), while T140 analogs ameliorated murine CIA (163). Numerous CCR1 and CCR2 antagonists have been developed in recent years (164-169). 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 non-specific compounds or specific inhibitors may control synovial inflammation.

7. ACKNOWLEDGEMENT

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.).

8. REFERENCES

1. A. E. Koch: Review: angiogenesis: implications for rheumatoid arthritis. Arthritis Rheum 41, 951-962 (1998)
doi:10.1002/1529-0131(199806)41:6<951::AID-ART2>3.0.CO;2-D

2. A. E. Koch: Chemokines and their receptors in rheumatoid arthritis: future targets? Arthritis Rheum 52, 710-721 (2005)
doi:10.1002/art.20932

3. E. M. Paleolog and R. A. Fava: Angiogenesis in rheumatoid arthritis: implications for future therapeutic strategies. Springer Semin Immunopathol 20, 73-94 (1998)
doi:10.1007/BF00832000
PMid:9836370

4. E. H. Rudolph and J. M. Woods: Chemokine expression and regulation of angiogenesis in rheumatoid arthritis. Curr Pharm Des 11, 613-631 (2005)
doi:10.2174/1381612053381963
PMid:15720278

5. Z. Szekanecz and A. E. Koch: Chemokines and angiogenesis. Curr Opin Rheumatol 13, 202-208 (2001)
doi:10.1097/00002281-200105000-00009
PMid:11333349

6. Z. Szekanecz, J. Kim and A. E. Koch: Chemokines and chemokine receptors in rheumatoid arthritis. Seminars in Immunology 399, 1-7 (2002)

7. Z. Szekanecz and A. E. Koch: Vascular endothelium and immune responses: implications for inflammation and angiogenesis. Rheum Dis Clin North Am 30, 97-114 (2004)
doi:10.1016/S0889-857X(03)00116-9
PMid:15061570

8. Z. Szekanecz, L. Gaspar and A. E. Koch: Angiogenesis in rheumatoid arthritis. Front Biosci 10, 1739-1753 (2005)
doi:10.2741/1657
PMid:15769663

9. Z. Szekanecz, G. Szucs, S. Szanto and A. E. Koch: Chemokines in rheumatic diseases. Curr Drug Targets 7, 91-102 (2006)
doi:10.2174/138945006775270231
PMid:16454702

10. C. E. Vergunst and P. P. Tak: Chemokines: their role in rheumatoid arthritis. Curr Rheumatol Rep 7, 382-388 (2005)
doi:10.1007/s11926-005-0026-7
PMid:16174489

11. D. J. Veale and U. Fearon: Inhibition of angiogenic pathways in rheumatoid arthritis: potential for therapeutic targeting. Best Pract Res Clin Rheumatol 20, 941-947 (2006)
doi:10.1016/j.berh.2006.05.004

12. M. Milkiewicz, E. Ispanovic, J. L. Doyle and T. L. Haas: Regulators of angiogenesis and strategies for their therapeutic manipulation. Int J Biochem Cell Biol 38, 333-357 (2006)
doi:10.1016/j.biocel.2005.10.006

13. K. Bacon, M. Baggiolini, H. Broxmeyer, R. Horuk, I. Lindley, A. Mantovani, K. Maysushima, P. Murphy, H. Nomiyama, J. Oppenheim, A. Rot, T. Schall, M. Tsang, R. Thorpe, J. Van Damme, M. Wadhwa, O. Yoshie, A. Zlotnik and K. Zoon: Chemokine/chemokine receptor nomenclature. J Interferon Cytokine Res 22, 1067-1068 (2002)
doi:10.1089/107999002760624305

14. D. D. Taub: C-C chemokines - an overview. 27-54 (1996)

15. A. Walz, S. L. Kunkel and R. M. Strieter: C-X-C chemokines - an overview. 1-25 (1996)

16. A. Zlotnik and O. Yoshie: Chemokines: a new classification system and their role in immunity. Immunity 12, 121-127 (2000)
doi:10.1016/S1074-7613(00)80165-X
PMid:10714678

17. R. M. Strieter, P. J. Polverini, S. L. Kunkel, D. A. Arenberg, M. D. Burdick, J. Kasper, J. Dzuiba, J. Van Damme, A. Walz, D. Marriott and .: The functional role of the ELR motif in CXC chemokine-mediated angiogenesis. J Biol Chem 270, 27348-27357 (1995)
doi:10.1074/jbc.270.45.27348
PMid:7592998

18. B. Deleuran, P. Lemche, M. Kristensen, C. Q. Chu, M. Field, J. Jensen, K. Matsushima and K. Stengaard-Pedersen: Localisation of interleukin 8 in the synovial membrane, cartilage-pannus junction and chondrocytes in rheumatoid arthritis. Scand J Rheumatol 23, 2-7 (1994)
doi:10.3109/03009749409102126
PMid:8108662

19. S. Hosaka, T. Akahoshi, C. Wada and H. Kondo: Expression of the chemokine superfamily in rheumatoid arthritis. Clin Exp Immunol 97, 451-457 (1994)

20. A. E. Koch, S. L. Kunkel, J. C. Burrows, H. L. Evanoff, G. K. Haines, R. M. Pope and R. M. Strieter: Synovial tissue macrophage as a source of the chemotactic cytokine IL-8. J Immunol 147, 2187-2195 (1991)

21. A. E. Koch, S. L. Kunkel, L. A. Harlow, D. D. Mazarakis, G. K. Haines, M. D. Burdick, R. M. Pope, A. Walz and R. M. Strieter: Epithelial neutrophil activating peptide-78: a novel chemotactic cytokine for neutrophils in arthritis. J Clin Invest 94, 1012-1018 (1994)
doi:10.1172/JCI117414
PMid:8083342    PMCid:295150

22. A. E. Koch, S. L. Kunkel, M. R. Shah, S. Hosaka, M. M. Halloran, G. K. Haines, M. D. Burdick, R. M. Pope and R. M. Strieter: Growth-related gene product alpha. A chemotactic cytokine for neutrophils in rheumatoid arthritis. J Immunol 155, 3660-3666 (1995)

23. A. E. Koch, M. V. Volin, J. M. Woods, S. L. Kunkel, M. A. Connors, L. A. Harlow, D. C. Woodruff, M. D. Burdick and R. M. Strieter: Regulation of angiogenesis by the C-X-C chemokines interleukin-8 and epithelial neutrophil activating peptide 78 in the rheumatoid joint. Arthritis Rheum 44, 31-40 (2001)
doi:10.1002/1529-0131(200101)44:1<31::AID-ANR5>3.0.CO;2-4

24. Z. Szekanecz and A. E. Koch: Macrophages and their products in rheumatoid arthritis. Curr Opin Rheumatol 19, 289-295 (2007)
doi:10.1097/BOR.0b013e32805e87ae
PMid:17414958

25. A. Konig, V. Krenn, A. Toksoy, N. Gerhard and R. Gillitzer: 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 436, 449-458 (2000)
doi:10.1007/s004280050472
PMid:10881738

26. C. Georganas, H. Liu, H. Perlman, A. Hoffmann, B. Thimmapaya and R. M. Pope: 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 165, 7199-7206 (2000)

27. A. M. Patterson, L. Gardner, J. Shaw, G. David, E. Loreau, L. Aguilar, B. A. Ashton and J. Middleton: Induction of a CXCL8 binding site on endothelial syndecan-3 in rheumatoid synovium. Arthritis Rheum 52, 2331-2342 (2005)
doi:10.1002/art.21222

28. Y. Chen, B. L. Davidson and R. M. Marks: Adenovirus-mediated transduction of the interleukin 8 gene into synoviocytes. Arthritis Rheum 37, S304 (1994)

29. M. M. Halloran, J. M. Woods, R. M. Strieter, Z. Szekanecz, M. V. Volin, S. Hosaka, G. K. Haines, III, S. L. Kunkel, M. D. Burdick, A. Walz and A. E. Koch: The role of an epithelial neutrophil-activating peptide-78-like protein in rat adjuvant-induced arthritis. J Immunol 162, 7492-7500 (1999)

30. E. N. Unemori, E. P. Amento, E. A. Bauer and R. Horuk: 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 (1993)

31. C. W. Castor, E. M. Smith, P. A. Hossler, M. C. Bignall and B. P. Aaron: 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 35, 783-793 (1992)
doi:10.1002/art.1780350712

32. C. W. Castor, P. C. Andrews, R. D. Swartz, S. G. Ellis, P. A. Hossler, M. R. Clark, E. L. Matteson and E. F. Sachter: 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 36, 1142-1153 (1993)
doi:10.1002/art.1780360816

33. M. Pierer, J. Rethage, R. Seibl, R. Lauener, F. Brentano, U. Wagner, H. Hantzschel, B. A. Michel, R. E. Gay, S. Gay and D. Kyburz: Chemokine secretion of rheumatoid arthritis synovial fibroblasts stimulated by Toll-like receptor 2 ligands. J Immunol 172, 1256-1265 (2004)

34. M. C. Blades, F. Ingegnoli, S. K. Wheller, A. Manzo, S. Wahid, G. S. Panayi, M. Perretti and C. Pitzalis: Stromal cell-derived factor 1 (CXCL12) induces monocyte migration into human synovium transplanted onto SCID Mice. Arthritis Rheum 46, 824-836 (2002)
doi:10.1002/art.10102

35. R. Hanaoka, T. Kasama, M. Muramatsu, N. Yajima, F. Shiozawa, Y. Miwa, M. Negishi, H. Ide, H. Miyaoka, H. Uchida and M. Adachi: A novel mechanism for the regulation of IFN-gamma inducible protein-10 expression in rheumatoid arthritis. Arthritis Res Ther 5, R74-R81 (2003)
doi:10.1186/ar616

36. D. D. Patel, J. P. Zachariah and L. P. Whichard: CXCR3 and CCR5 ligands in rheumatoid arthritis synovium. Clin Immunol 98, 39-45 (2001)
doi:10.1006/clim.2000.4957
PMid:11141325

37. P. F. Bradfield, N. Amft, E. Vernon-Wilson, A. E. Exley, G. Parsonage, G. E. Rainger, G. B. Nash, A. M. Thomas, D. L. Simmons, M. Salmon and C. D. Buckley: 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 48, 2472-2482 (2003)
doi:10.1002/art.11219

38. I. B. Hansen, T. Ellingsen, N. Hornung, J. H. Poulsen, T. Lottenburger and K. Stengaard-Pedersen: Plasma level of CXC-chemokine CXCL12 is increased in rheumatoid arthritis and is independent of disease activity and methotrexate treatment. J Rheumatol 33, 1754-1759 (2006)

39. T. Nanki, K. Hayashida, H. S. El Gabalawy, S. Suson, K. Shi, H. J. Girschick, S. Yavuz and P. E. Lipsky: 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 165, 6590-6598 (2000)

40. C. D. Buckley: Michael Mason prize essay 2003. Why do leucocytes accumulate within chronically inflamed joints? Rheumatology (Oxford) 42, 1433-1444 (2003)
doi:10.1093/rheumatology/keg413
PMid:12832715

41. K. W. Kim, M. L. Cho, H. R. Kim, J. H. Ju, M. K. Park, H. J. Oh, J. S. Kim, S. H. Park, S. H. Lee and H. Y. Kim: 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 56, 1076-1086 (2007)
doi:10.1002/art.22439

42. S. Gronthos and A. C. Zannettino: The role of the chemokine CXCL12 in osteoclastogenesis. Trends Endocrinol Metab 18, 108-113 (2007)
doi:10.1016/j.tem.2007.02.002

43. B. Joven, N. Gonzalez, F. Aguilar, B. Santiago, M. Galindo, J. Alcami and J. L. Pablos: Association between stromal cell-derived factor 1 chemokine gene variant and radiographic progression of rheumatoid arthritis. Arthritis Rheum 52, 354-356 (2005)
doi:10.1002/art.20743

44. B. Santiago, F. Baleux, G. Palao, I. Gutierrez-Canas, J. C. Ramirez, F. Arenzana-Seisdedos and J. L. Pablos: CXCL12 is displayed by rheumatoid endothelial cells through its basic amino-terminal motif on heparan sulfate proteoglycans. Arthritis Res Ther 8, R43 (2006)
doi:10.1186/ar1900

45. S. De Vita, F. Zaja, S. Sacco, A. De Candia, R. Fanin and G. Ferraccioli: Efficacy of selective B cell blockade in the treatment of rheumatoid arthritis: evidence for a pathogenetic role of B cells. Arthritis Rheum 46, 2029-2033 (2002)
doi:10.1002/art.10467

46. J. C. Edwards, G. Cambridge and V. M. Abrahams: Do self-perpetuating B lymphocytes drive human autoimmune disease? Immunology 97, 188-196 (1999)
doi:10.1046/j.1365-2567.1999.00772.x
PMid:10447731    PMCid:2326840

47. G. J. Silverman and D. A. Carson: Roles of B cells in rheumatoid arthritis. Arthritis Res Ther 5 Suppl 4, S1-S6 (2003)
doi:10.1186/ar1010

48. A. Manzo, S. Paoletti, M. Carulli, M. C. Blades, F. Barone, G. Yanni, O. Fitzgerald, B. Bresnihan, R. Caporali, C. Montecucco, M. Uguccioni and C. Pitzalis: Systematic microanatomical analysis of CXCL13 and CCL21 in situ production and progressive lymphoid organization in rheumatoid synovitis. Eur J Immunol 35, 1347-1359 (2005)
doi:10.1002/eji.200425830
PMid:15832291

49. T. Nanki, T. Shimaoka, K. Hayashida, K. Taniguchi, S. Yonehara and N. Miyasaka: Pathogenic role of the CXCL16-CXCR6 pathway in rheumatoid arthritis. Arthritis Rheum 52, 3004-3014 (2005)
doi:10.1002/art.21301

50. J. H. Ruth, C. S. Haas, C. C. Park, M. A. Amin, R. J. Martinez, G. K. Haines, III, S. Shahrara, P. L. Campbell and A. E. Koch: CXCL16-mediated cell recruitment to rheumatoid arthritis synovial tissue and murine lymph nodes is dependent upon the MAPK pathway. Arthritis Rheum 54, 765-778 (2006)
doi:10.1002/art.21662

51. d. van, V, A. W. van Lieshout, L. W. Toonen, A. W. Sloetjes, W. B. van den Berg, C. G. Figdor, T. R. Radstake and G. J. Adema: Elevated CXCL16 expression by synovial macrophages recruits memory T cells into rheumatoid joints. Arthritis Rheum 52, 1381-1391 (2005)

52. A. E. Koch, S. L. Kunkel, L. A. Harlow, B. Johnson, H. L. Evanoff, G. K. Haines, M. D. Burdick, R. M. Pope and R. M. Strieter: Enhanced production of monocyte chemoattractant protein-1 in rheumatoid arthritis. J Clin Invest 90, 772-779 (1992)
doi:10.1172/JCI115950
PMid:1522232    PMCid:329929

53. P. M. Villiger, R. Terkeltaub and M. Lotz: Production of monocyte chemoattractant protein-1 by inflamed synovial tissue and cultured synoviocytes. J Immunol 149, 722-727 (1992)

54. M. V. Volin, M. R. Shah, M. Tokuhira, G. K. Haines, J. M. Woods and A. E. Koch: RANTES expression and contribution to monocyte chemotaxis in arthritis. Clin Immunol Immunopathol 89, 44-53 (1998)
doi:10.1006/clin.1998.4590
PMid:9756723

55. P. Rathanaswami, M. Hachicha, M. Sadick, T. J. Schall and S. R. McColl: 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 (1993)

56. J. K. Yoo, H. Kwon, L. Y. Khil, L. Zhang, H. S. Jun and J. W. Yoon: IL-18 induces monocyte chemotactic protein-1 production in macrophages through the phosphatidylinositol 3-kinase/Akt and MEK/ERK1/2 pathways. J Immunol 175, 8280-8286 (2005)

57. O. Safronova, K. Nakahama, M. Onodera, T. Muneta and I. Morita: Effect of hypoxia on monocyte chemotactic protein-1 (MCP-1) gene expression induced by Interleukin-1beta in human synovial fibroblasts. Inflamm Res 52, 480-486 (2003)
doi:10.1007/s00011-003-1205-5
PMid:14652683

58. T. Akahoshi, C. Wada, H. Endo, K. Hirota, S. Hosaka, K. Takagishi, H. Kondo, S. Kashiwazaki and K. Matsushima: 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 36, 762-771 (1993)
doi:10.1002/art.1780360605

59. H. Hounoki, E. Sugiyama, S. G. Mohamed, K. Shinoda, H. Taki, H. O. Abdel-Aziz, M. Maruyama, M. Kobayashi and T. Miyahara: 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 42, 765-774 (2008)
doi:10.1016/j.bone.2007.11.016
PMid:18242157

60. A. E. Koch, S. L. Kunkel, L. A. Harlow, D. D. Mazarakis, G. K. Haines, M. D. Burdick, R. M. Pope and R. M. Strieter: Macrophage inflammatory protein-1 alpha. A novel chemotactic cytokine for macrophages in rheumatoid arthritis. J Clin Invest 93, 921-928 (1994)
doi:10.1172/JCI117097
PMid:8132778    PMCid:293992

61. C. R. Wang and M. F. Liu: Regulation of CCR5 expression and MIP-1alpha production in CD4+ T cells from patients with rheumatoid arthritis. Clin Exp Immunol 132, 371-378 (2003)
doi:10.1046/j.1365-2249.2003.02126.x

62. C. R. Wang, H. R. Guo and M. F. Liu: RANTES promoter polymorphism as a genetic risk factor for rheumatoid arthritis in the Chinese. Clin Exp Rheumatol 23, 379-384 (2005)

63. T. Matsui, T. Akahoshi, R. Namai, A. Hashimoto, Y. Kurihara, M. Rana, A. Nishimura, H. Endo, H. Kitasato, S. Kawai, K. Takagishi and H. Kondo: Selective recruitment of CCR6-expressing cells by increased production of MIP-3 alpha in rheumatoid arthritis. Clin Exp Immunol 125, 155-161 (2001)
doi:10.1046/j.1365-2249.2001.01542.x

64. M. Chabaud, G. Page and P. Miossec: 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 167, 6015-6020 (2001)

65. J. H. Ruth, J. C. M. Morel, C. C. Park and A. E. Koch: MIP-3a expression in the rheumatoid joint. Arthritis Rheum 43, S78 (2000)

66. J. Schlenk, H. M. Lorenz, J. P. Haas, M. Herrmann, G. Hohenberger, J. R. Kalden, M. Rollinghoff and H. U. Beuscher: Extravasation into synovial tissue induces CCL20 mRNA expression in polymorphonuclear neutrophils of patients with rheumatoid arthritis. J Rheumatol 32, 2291-2298 (2005)

67. K. Hirota, H. Yoshitomi, M. Hashimoto, S. Maeda, S. Teradaira, N. Sugimoto, T. Yamaguchi, T. Nomura, H. Ito, T. Nakamura, N. Sakaguchi and S. Sakaguchi: Preferential recruitment of CCR6-expressing Th17 cells to inflamed joints via CCL20 in rheumatoid arthritis and its animal model. J Exp Med 204, 2803-2812 (2007)
doi:10.1084/jem.20071397
PMid:18025126    PMCid:2118525

68. G. Lisignoli, A. Piacentini, S. Cristino, F. Grassi, C. Cavallo, L. Cattini, B. Tonnarelli, C. Manferdini and A. Facchini: 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 210, 798-806 (2007)
doi:10.1002/jcp.20905
PMid:17133360

69. A. W. van Lieshout, J. Fransen, M. Flendrie, A. M. Eijsbouts, F. H. van den Hoogen, P. L. van Riel and T. R. Radstake: Circulating levels of the chemokine CCL18 but not CXCL16 are elevated and correlate with disease activity in rheumatoid arthritis. Ann Rheum Dis 66, 1334-1338 (2007)
doi:10.1136/ard.2006.066084
PMid:17350968

70. J. Auer, M. Blass, H. Schulze-Koops, S. Russwurm, T. Nagel, J. R. Kalden, M. Rollinghoff and H. U. Beuscher: Expression and regulation of CCL18 in synovial fluid neutrophils of patients with rheumatoid arthritis. Arthritis Res Ther 9, R94 (2007)
doi:10.1186/ar2294

71. T. Iwamoto, H. Okamoto, S. Kobayashi, K. Ikari, Y. Toyama, T. Tomatsu, N. Kamatani and S. Momohara: A role of monocyte chemoattractant protein-4 (MCP-4)/CCL13 from chondrocytes in rheumatoid arthritis. FEBS J 274, 4904-4912 (2007)
doi:10.1111/j.1742-4658.2007.06013.x
PMid:17824960

72. A. Manzo, S. Bugatti, R. Caporali, R. Prevo, D. G. Jackson, M. Uguccioni, C. D. Buckley, C. Montecucco and C. Pitzalis: CCL21 expression pattern of human secondary lymphoid organ stroma is conserved in inflammatory lesions with lymphoid neogenesis. Am J Pathol 171, 1549-1562 (2007)
doi:10.2353/ajpath.2007.061275
PMid:17982129    PMCid:2043516

73. S. Momohara, H. Okamoto, T. Iwamoto, T. Mizumura, K. Ikari, Y. Kawaguchi, M. Takeuchi, N. Kamatani and T. Tomatsu: High CCL18/PARC expression in articular cartilage and synovial tissue of patients with rheumatoid arthritis. J Rheumatol 34, 266-271 (2007)

74. H. Okamoto, K. Koizumi, H. Yamanaka, T. Saito and N. Kamatani: A role for TARC/CCL17, a CC chemokine, in systemic lupus erythematosus. J Rheumatol 30, 2369-2373 (2003)

75. A. W. van Lieshout, d. van, V, L. M. le Blanc, M. F. Roelofs, B. W. Schreurs, P. L. van Riel, G. J. Adema and T. R. Radstake: Novel insights in the regulation of CCL18 secretion by monocytes and dendritic cells via cytokines, toll-like receptors and rheumatoid synovial fluid. BMC Immunol 7, 23 (2006)
doi:10.1186/1471-2172-7-23
PMid:16984635    PMCid:1590050

76. J. J. Haringman, T. J. Smeets, P. Reinders-Blankert and P. P. Tak: 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 65, 294-300 (2006)
doi:10.1136/ard.2005.037176
PMid:16107514    PMCid:1798063

77. T. Li, J. Zhong, Y. Chen, X. Qiu, T. Zhang, D. Ma and W. Han: Expression of chemokine-like factor 1 is upregulated during T lymphocyte activation. Life Sci 79, 519-524 (2006)
doi:10.1016/j.lfs.2006.01.042
PMid:16522323

78. S. Blaschke, P. Middel, B. G. Dorner, V. Blaschke, K. M. Hummel, R. A. Kroczek, K. Reich, P. Benoehr, M. Koziolek and G. A. Muller: Expression of activation-induced, T cell-derived, and chemokine-related cytokine/lymphotactin and its functional role in rheumatoid arthritis. Arthritis Rheum 48, 1858-1872 (2003)
doi:10.1002/art.11171

79. N. J. Borthwick, A. N. Akbar, L. P. MacCormac, M. Lowdell, J. L. Craigen, I. Hassan, J. E. Grundy, M. Salmon and K. L. Yong: 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 90, 272-280 (1997)
doi:10.1046/j.1365-2567.1997.00154.x
PMid:9135557    PMCid:1456733

80. J. F. Bazan, K. B. Bacon, G. Hardiman, W. Wang, K. Soo, D. Rossi, D. R. Greaves, A. Zlotnik and T. J. Schall: A new class of membrane-bound chemokine with a CX3C motif. Nature 385, 640-644 (1997)
doi:10.1038/385640a0
PMid:9024663

81. P. Loetscher, M. Uguccioni, L. Bordoli, M. Baggiolini, B. Moser, C. Chizzolini and J. M. Dayer: CCR5 is characteristic of Th1 lymphocytes. Nature 391, 344-345 (1998)
doi:10.1038/34814
PMid:9450746

82. J. H. Ruth, M. V. Volin, G. K. Haines, III, D. C. Woodruff, K. J. Katschke, Jr., J. M. Woods, C. C. Park, J. C. Morel and A. E. Koch: Fractalkine, a novel chemokine in rheumatoid arthritis and in rat adjuvant-induced arthritis. Arthritis Rheum 44, 1568-1581 (2001)
doi:10.1002/1529-0131(200107)44:7<1568::AID-ART280>3.0.CO;2-1

83. H. Sawai, Y. W. Park, J. Roberson, T. Imai, J. J. Goronzy and C. M. Weyand: T cell costimulation by fractalkine-expressing synoviocytes in rheumatoid arthritis. Arthritis Rheum 52, 1392-1401 (2005)
doi:10.1002/art.21140

84. H. Sawai, Y. W. Park, X. He, J. J. Goronzy and C. M. Weyand: Fractalkine mediates T cell-dependent proliferation of synovial fibroblasts in rheumatoid arthritis. Arthritis Rheum 56, 3215-3225 (2007)
doi:10.1002/art.22919

85. M. V. Volin, N. Huynh, K. Klosowska, K. K. Chong and J. M. Woods: Fractalkine is a novel chemoattractant for rheumatoid arthritis fibroblast-like synoviocyte signaling through MAP kinases and Akt. Arthritis Rheum 56, 2512-2522 (2007)
doi:10.1002/art.22806

86. M. Matsunawa, T. Isozaki, T. Odai, N. Yajima, H. T. Takeuchi, M. Negishi, H. Ide, M. Adachi and T. Kasama: Increased serum levels of soluble fractalkine (CX3CL1) correlate with disease activity in rheumatoid vasculitis. Arthritis Rheum 54, 3408-3416 (2006)
doi:10.1002/art.22208

87. D. H. McDermott, A. M. Fong, Q. Yang, J. M. Sechler, L. A. Cupples, M. N. Merrell, P. W. Wilson, R. B. D'Agostino, C. J. O'Donnell, D. D. Patel and P. M. Murphy: Chemokine receptor mutant CX3CR1-M280 has impaired adhesive function and correlates with protection from cardiovascular disease in humans. J Clin Invest 111, 1241-1250 (2003)

88. E. Pingiotti, P. Cipriani, A. Marrelli, V. Liakouli, S. Fratini, M. Penco and R. Giacomelli: Surface expression of fractalkine receptor (CX3CR1) on CD4+/CD28 T cells in RA patients and correlation with atherosclerotic damage. Ann N Y Acad Sci 1107, 32-41 (2007)
doi:10.1196/annals.1381.004
PMid:17804530

89. M. V. Volin, J. M. Woods, M. A. Amin, M. A. Connors, L. A. Harlow and A. E. Koch: Fractalkine: a novel angiogenic chemokine in rheumatoid arthritis. Am J Pathol 159, 1521-1530 (2001)

90. M. A. Garcia-Lopez, F. Sanchez-Madrid, J. M. Rodriguez-Frade, M. Mellado, A. Acevedo, M. I. Garcia, J. P. Albar, C. Martinez and M. Marazuela: CXCR3 chemokine receptor distribution in normal and inflamed tissues: expression on activated lymphocytes, endothelial cells, and dendritic cells. Lab Invest 81, 409-418 (2001)

91. S. Qin, J. B. Rottman, P. Myers, N. Kassam, M. Weinblatt, M. Loetscher, A. E. Koch, B. Moser and C. R. Mackay: The chemokine receptors CXCR3 and CCR5 mark subsets of T cells associated with certain inflammatory reactions. J Clin Invest 101, 746-754 (1998)
doi:10.1172/JCI1422
PMid:9466968    PMCid:508621

92. L. R. Wedderburn, N. Robinson, A. Patel, H. Varsani and P. Woo: Selective recruitment of polarized T cells expressing CCR5 and CXCR3 to the inflamed joints of children with juvenile idiopathic arthritis. Arthritis Rheum 43, 765-774 (2000)
doi:10.1002/1529-0131(200004)43:4<765::AID-ANR7>3.0.CO;2-B

93. C. Schmutz, A. Hulme, A. Burman, M. Salmon, B. Ashton, C. Buckley and J. Middleton: Chemokine receptors in the rheumatoid synovium: upregulation of CXCR5. Arthritis Res Ther 7, R217-R229 (2005)
doi:10.1186/ar1475

94. J. H. Ruth, J. B. Rottman, K. J. Katschke, Jr., S. Qin, L. Wu, G. LaRosa, P. Ponath, R. M. Pope and A. E. Koch: Selective lymphocyte chemokine receptor expression in the rheumatoid joint. Arthritis Rheum 44, 2750-2760 (2001)
doi:10.1002/1529-0131(200112)44:12<2750::AID-ART462>3.0.CO;2-C

95. A. M. Wengner, U. E. Hopken, P. K. Petrow, S. Hartmann, U. Schurigt, R. Brauer and M. Lipp: CXCR5 and CCR7 dependent lymphoid neogenesis in a murine model of chronic antigen-induced arthritis. Arthritis Rheum 56, 3271-3283 (2007)
doi:10.1002/art.22939

96. B. Moser and P. Loetscher: Lymphocyte traffic control by chemokines. Nat Immunol 2, 123-128 (2001)
doi:10.1038/84219
PMid:11175804

97. K. J. Katschke, Jr., J. B. Rottman, J. H. Ruth, S. Qin, L. Wu, G. LaRosa, P. Ponath, C. C. Park, R. M. Pope and A. E. Koch: Differential expression of chemokine receptors on peripheral blood, synovial fluid, and synovial tissue monocytes/macrophages in rheumatoid arthritis. Arthritis Rheum 44, 1022-1032 (2001)
doi:10.1002/1529-0131(200105)44:5<1022::AID-ANR181>3.0.CO;2-N

98. R. M. Borzi, I. Mazzetti, L. Cattini, M. Uguccioni, M. Baggiolini and A. Facchini: 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 (2000)
doi:10.1002/1529-0131(200008)43:8<1734::AID-ANR9>3.0.CO;2-B

99. S. Prahalad: Negative association between the chemokine receptor CCR5-Delta32 polymorphism and rheumatoid arthritis: a meta-analysis. Genes Immun 7, 264-268 (2006)
doi:10.1038/sj.gene.6364298
PMid:16541097

100. C. L. Kohem, J. C. Brenol, R. M. Xavier, M. Bredemeier, C. V. Brenol, Dedavid e Silva TL, M. A. de Castilhos, A. D. Canedo, A. G. Neves and J. A. Chies: The chemokine receptor CCR5 genetic polymorphism and expression in rheumatoid arthritis patients. Scand J Rheumatol 36, 359-364 (2007)
doi:10.1080/03009740701393999
PMid:17963165

101. E. Lindner, G. B. Nordang, E. Melum, B. Flato, A. M. Selvaag, E. Thorsby, T. K. Kvien, O. T. Forre and B. A. Lie: Lack of association between the chemokine receptor 5 polymorphism CCR5delta32 in rheumatoid arthritis and juvenile idiopathic arthritis. BMC Med Genet 8, 33 (2007)
doi:10.1186/1471-2350-8-33
PMid:17565662    PMCid:1906748

102. C. L. Galligan, W. Matsuyama, A. Matsukawa, H. Mizuta, D. R. Hodge, O. M. Howard and T. Yoshimura: Up-regulated expression and activation of the orphan chemokine receptor, CCRL2, in rheumatoid arthritis. Arthritis Rheum 50, 1806-1814 (2004)
doi:10.1002/art.20275

103. J. L. Pablos, B. Santiago, M. Galindo, C. Torres, M. T. Brehmer, F. J. Blanco and F. J. Garcia-Lazaro: Synoviocyte-derived CXCL12 is displayed on endothelium and induces angiogenesis in rheumatoid arthritis. J Immunol 170, 2147-2152 (2003)

104. P. H. Wooley, C. Schaefer, J. D. Whalen, J. A. Dutcher and D. F. Counts: A peptide sequence from platelet factor 4 (CT-112) is effective in the treatment of type II collagen induced arthritis in mice. J Rheumatol 24, 890-898 (1997)

105. M. Norii, M. Yamamura, M. Iwahashi, A. Ueno, J. Yamana and H. Makino: Selective recruitment of CXCR3+ and CCR5+ CCR4+ T cells into synovial tissue in patients with rheumatoid arthritis. Acta Med Okayama 60, 149-157 (2006)

106. M. Caunt, L. Hu, T. Tang, P. C. Brooks, S. Ibrahim and S. Karpatkin: Growth-regulated oncogene is pivotal in thrombin-induced angiogenesis. Cancer Res 66, 4125-4132 (2006)
doi:10.1158/0008-5472.CAN-05-2570
PMid:16618733

107. Z. Liang, J. Brooks, M. Willard, K. Liang, Y. Yoon, S. Kang and H. Shim: CXCR4/CXCL12 axis promotes VEGF-mediated tumor angiogenesis through Akt signaling pathway. Biochem Biophys Res Commun 359, 716-722 (2007)
doi:10.1016/j.bbrc.2007.05.182
PMid:17559806    PMCid:1986788

108. I. Petit, D. Jin and S. Rafii: The SDF-1-CXCR4 signaling pathway: a molecular hub modulating neo-angiogenesis. Trends Immunol 28, 299-307 (2007)
doi:10.1016/j.it.2007.05.007
PMid:17560169

109. C. Calatozzolo, E. Maderna, B. Pollo, M. Gelati, C. Marras, A. Silvani, D. Croci, A. Boiardi and A. Salmaggi: Prognostic value of CXCL12 expression in 40 low-grade oligodendrogliomas and oligoastrocytomas. Cancer Biol Ther 5, 827-832 (2006)

110. R. J. Bodnar, C. C. Yates and A. Wells: IP-10 blocks vascular endothelial growth factor-induced endothelial cell motility and tube formation via inhibition of calpain. Circ Res 98, 617-625 (2006)
doi:10.1161/01.RES.0000209968.66606.10
PMid:16484616

111. G. Boulday, Z. Haskova, M. E. Reinders, S. Pal and D. M. Briscoe: 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 176, 3098-3107 (2006)

112. A. M. Maurer, B. Zhou and Z. C. Han: Roles of platelet factor 4 in hematopoiesis and angiogenesis. Growth Factors 24, 242-252 (2006)
doi:10.1080/08977190600988225
PMid:17381065

113. R. Salcedo, M. L. Ponce, H. A. Young, K. Wasserman, J. M. Ward, H. K. Kleinman, J. J. Oppenheim and W. J. Murphy: Human endothelial cells express CCR2 and respond to MCP-1: direct role of MCP-1 in angiogenesis and tumor progression. Blood 96, 34-40 (2000)

114. S. M. Stamatovic, R. F. Keep, M. Mostarica-Stojkovic and A. V. Andjelkovic: CCL2 regulates angiogenesis via activation of Ets-1 transcription factor. J Immunol 177, 2651-2661 (2006)

115. K. N. Son, J. Hwang, B. S. Kwon and J. Kim: Human CC chemokine CCL23 enhances expression of matrix metalloproteinase-2 and invasion of vascular endothelial cells. Biochem Biophys Res Commun 340, 498-504 (2006)
doi:10.1016/j.bbrc.2005.12.037
PMid:16378600

116. A. P. Vicari, S. Ait-Yahia, K. Chemin, A. Mueller, A. Zlotnik and C. Caux: Antitumor effects of the mouse chemokine 6Ckine/SLC through angiostatic and immunological mechanisms. J Immunol 165, 1992-2000 (2000)

117. C. D. Buckley, N. Amft, P. F. Bradfield, D. Pilling, E. Ross, F. Arenzana-Seisdedos, A. Amara, S. J. Curnow, J. M. Lord, D. Scheel-Toellner and M. Salmon: 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 165, 3423-3429 (2000)

118. D. Zagzag, Y. Lukyanov, L. Lan, M. A. Ali, M. Esencay, O. Mendez, H. Yee, E. B. Voura and E. W. Newcomb: Hypoxia-inducible factor 1 and VEGF upregulate CXCR4 in glioblastoma: implications for angiogenesis and glioma cell invasion. Lab Invest 86, 1221-1232 (2006)
doi:10.1038/labinvest.3700482
PMid:17075581

119. J. M. Burns, B. C. Summers, Y. Wang, A. Melikian, R. Berahovich, Z. Miao, M. E. Penfold, M. J. Sunshine, D. R. Littman, C. J. Kuo, K. Wei, B. E. McMaster, K. Wright, M. C. Howard and T. J. Schall: A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development. J Exp Med 203, 2201-2213 (2006)
doi:10.1084/jem.20052144
PMid:16940167    PMCid:2118398

120. O. Ochoa, D. Sun, S. M. Reyes-Reyna, L. L. Waite, J. E. Michalek, L. M. McManus and P. K. Shireman: Delayed angiogenesis and VEGF production in CCR2-/- mice during impaired skeletal muscle regeneration. Am J Physiol Regul Integr Comp Physiol 293, R651-R661 (2007)
doi:10.1152/ajpregu.00069.2007

121. P. Lesnik, C. A. Haskell and I. F. Charo: Decreased atherosclerosis in CX3CR1-/- mice reveals a role for fractalkine in atherogenesis. J Clin Invest 111, 333-340 (2003)

122. Z. Szekanecz, M. M. Halloran, M. V. Volin, J. M. Woods, R. M. Strieter, H. G. Kenneth, III, S. L. Kunkel, M. D. Burdick and A. E. Koch: Temporal expression of inflammatory cytokines and chemokines in rat adjuvant-induced arthritis. Arthritis Rheum 43, 1266-1277 (2000)
doi:10.1002/1529-0131(200006)43:6<1266::AID-ANR9>3.0.CO;2-P

123. C. S. Haas, R. J. Martinez, N. Attia, G. K. Haines, III, P. L. Campbell and A. E. Koch: Chemokine receptor expression in rat adjuvant-induced arthritis. Arthritis Rheum 52, 3718-3730 (2005)
doi:10.1002/art.21476

124. M. Feldmann, F. M. Brennan and R. N. Maini: Role of cytokines in rheumatoid arthritis. Annu Rev Immunol 14, 397-440 (1996)
doi:10.1146/annurev.immunol.14.1.397
PMid:8717520

125. Z. Szekanecz, A. E. Koch, S. L. Kunkel and R. M. Strieter: Cytokines in rheumatoid arthritis. Potential targets for pharmacological intervention. Drugs Aging 12, 377-390 (1998)

126. T. J. Fahey, III, K. J. Tracey, P. Tekamp-Olson, L. S. Cousens, W. G. Jones, G. T. Shires, A. Cerami and B. Sherry: Macrophage inflammatory protein 1 modulates macrophage function. J Immunol 148, 2764-2769 (1992)

127. P. P. Tak: Chemokine inhibition in inflammatory arthritis. Best Pract Res Clin Rheumatol 20, 929-939 (2006)
doi:10.1016/j.berh.2006.06.001

128. M. J. Lopez-Armada, O. Sanchez-Pernaute, R. Largo, I. Diez-Ortego, I. Palacios, J. Egido and G. Herrero-Beaumont: Modulation of cell recruitment by anti-inflammatory agents in antigen-induced arthritis. Ann Rheum Dis 61, 1027-1030 (2002)
doi:10.1136/ard.61.11.1027
PMid:12379530    PMCid:1753940

129. P. Loetscher, B. Dewald, M. Baggiolini and M. Seitz: Monocyte chemoattractant protein 1 and interleukin 8 production by rheumatoid synoviocytes. Effects of anti-rheumatic drugs. Cytokine 6, 162-170 (1994)
doi:10.1016/1043-4666(94)90038-8
PMid:8031999

130. M. V. Volin, P. L. Campbell, M. A. Connors, D. C. Woodruff and A. E. Koch: The effect of sulfasalazine on rheumatoid arthritic synovial tissue chemokine production. Exp Mol Pathol 73, 84-92 (2002)
doi:10.1006/exmp.2002.2460
PMid:12231210

131. M. V. Volin, L. A. Harlow, J. M. Woods, P. L. Campbell, M. A. Amin, M. Tokuhira and A. E. Koch: Treatment with sulfasalazine or sulfapyridine, but not 5-aminosalicyclic acid, inhibits basic fibroblast growth factor-induced endothelial cell chemotaxis. Arthritis Rheum 42, 1927-1935 (1999)
doi:10.1002/1529-0131(199909)42:9<1927::AID-ANR19>3.0.CO;2-X

132. C. Y. Ho, C. K. Wong, E. K. Li, L. S. Tam and C. W. Lam: Suppressive effect of combination treatment of leflunomide and methotrexate on chemokine expression in patients with rheumatoid arthritis. Clin Exp Immunol 133, 132-138 (2003)
doi:10.1046/j.1365-2249.2003.02192.x

133. T. Ellingsen, N. Hornung, B. K. Moller, J. H. Poulsen and K. Stengaard-Pedersen: 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 66, 151-157 (2007)
doi:10.1136/ard.2006.054056
PMid:16905577

134. Y. Kageyama, E. Torikai and A. Nagano: Anti-tumor necrosis factor-alpha antibody treatment reduces serum CXCL16 levels in patients with rheumatoid arthritis. Rheumatol Int 27, 467-472 (2006)
doi:10.1007/s00296-006-0241-1
PMid:17051360

135. P. A. Klimiuk, S. Sierakowski, I. Domyslawska and J. Chwiecko: Regulation of serum chemokines following infliximab therapy in patients with rheumatoid arthritis. Clin Exp Rheumatol 24, 529-533 (2006)

136. P. C. Taylor, A. M. Peters, E. Paleolog, P. T. Chapman, M. J. Elliott, R. McCloskey, M. Feldmann and R. N. Maini: Reduction of chemokine levels and leukocyte traffic to joints by tumor necrosis factor alpha blockade in patients with rheumatoid arthritis. Arthritis Rheum 43, 38-47 (2000)
doi:10.1002/1529-0131(200001)43:1<38::AID-ANR6>3.0.CO;2-L

137. E. Torikai, Y. Kageyama, M. Suzuki, T. Ichikawa and A. Nagano: The effect of infliximab on chemokines in patients with rheumatoid arthritis. Clin Rheumatol 26, 1088-1093 (2007)
doi:10.1007/s10067-006-0453-5
PMid:17111092

138. R. Nissinen, M. Leirisalo-Repo, R. Peltomaa, T. Palosuo and O. Vaarala: Cytokine and chemokine receptor profile of peripheral blood mononuclear cells during treatment with infliximab in patients with active rheumatoid arthritis. Ann Rheum Dis 63, 681-687 (2004)
doi:10.1136/ard.2003.008599
PMid:15140775    PMCid:1755037

139. D. Aeberli, M. Seitz, P. Juni and P. M. Villiger: Increase of peripheral CXCR3 positive T lymphocytes upon treatment of RA patients with TNF-alpha inhibitors. Rheumatology (Oxford) 44, 172-175 (2005)
doi:10.1093/rheumatology/keh437
PMid:15509629

140. S. M. Newton, S. L. Mackie, A. R. Martineau, K. A. Wilkinson, B. Kampmann, C. Fisher, S. Dutta, M. Levin, R. J. Wilkinson and G. Pasvol: Reduction of chemokine secretion in response to mycobacteria in infliximab-treated patients. Clin Vaccine Immunol 15, 506-512 (2008)
doi:10.1128/CVI.00401-07
PMid:18160618

141. M. Sato, T. Miyazaki, T. Nagaya, Y. Murata, N. Ida, K. Maeda and H. Seo: 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 23, 432-438 (1996)

142. K. Yokota, T. Miyazaki, M. Hirano, Y. Akiyama and T. Mimura: Simvastatin inhibits production of interleukin 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 33, 463-471 (2006)

143. Y. Wang, D. Wei, Z. Lai and Y. Le: Triptolide inhibits CC chemokines expressed in rat adjuvant-induced arthritis. Int Immunopharmacol 6, 1825-1832 (2006)
doi:10.1016/j.intimp.2006.07.029
PMid:17052673

144. S. Ahmed, A. Pakozdi and A. E. Koch: Regulation of interleukin-1beta-induced chemokine production and matrix metalloproteinase 2 activation by epigallocatechin-3-gallate in rheumatoid arthritis synovial fibroblasts. Arthritis Rheum 54, 2393-2401 (2006)
doi:10.1002/art.22023

145. C. Ospelt, M. Kurowska-Stolarska, M. Neidhart, B. A. Michel, R. E. Gay, S. Laufer and S. Gay: The dual inhibitor of lipoxygenase and cyclooxygenase ML3000 decreases the expression of CXCR3 ligands. Ann Rheum Dis 67, 524-529 (2008)
doi:10.1136/ard.2007.071589
PMid:17666446

146. T. Akahoshi, H. Endo, H. Kondo, S. Kashiwazaki, T. Kasahara, N. Mukaida, A. Harada and K. Matsushima: Essential involvement of interleukin-8 in neutrophil recruitment in rabbits with acute experimental arthritis induced by lipopolysaccharide and interleukin-1. Lymphokine Cytokine Res 13, 113-116 (1994)

147. T. Kasama, R. M. Strieter, N. W. Lukacs, P. M. Lincoln, M. D. Burdick and S. L. Kunkel: Interleukin-10 expression and chemokine regulation during the evolution of murine type II collagen-induced arthritis. J Clin Invest 95, 2868-2876 (1995)
doi:10.1172/JCI117993
PMid:7769128    PMCid:295974

148. H. Ogata, M. Takeya, T. Yoshimura, K. Takagi and K. Takahashi: The role of monocyte chemoattractant protein-1 (MCP-1) in the pathogenesis of collagen-induced arthritis in rats. J Pathol 182, 106-114 (1997)
doi:10.1002/(SICI)1096-9896(199705)182:1<106::AID-PATH816>3.0.CO;2-A
PMid:9227349

149. D. J. Schrier, R. C. Schimmer, C. M. Flory, D. K. Tung and P. A. Ward: Role of chemokines and cytokines in a reactivation model of arthritis in rats induced by injection with streptococcal cell walls. J Leukoc Biol 63, 359-363 (1998)

150. S. Shahrara, A. E. Proudfoot, C. C. Park, M. V. Volin, G. K. Haines, J. M. Woods, C. H. Aikens, T. M. Handel and R. M. Pope: Inhibition of monocyte chemoattractant protein-1 ameliorates rat adjuvant-induced arthritis. J Immunol 180, 3447-3456 (2008)

151. J. H. Gong, L. G. Ratkay, J. D. Waterfield and I. Clark-Lewis: An antagonist of monocyte chemoattractant protein 1 (MCP-1) inhibits arthritis in the MRL-lpr mouse model. J Exp Med 186, 131-137 (1997)
doi:10.1084/jem.186.1.131
PMid:9207007    PMCid:2198969

152. D. A. Barnes, J. Tse, M. Kaufhold, M. Owen, J. Hesselgesser, R. Strieter, R. Horuk and H. D. Perez: Polyclonal antibody directed against human RANTES ameliorates disease in the Lewis rat adjuvant-induced arthritis model. J Clin Invest 101, 2910-2919 (1998)
doi:10.1172/JCI2172
PMid:9637726    PMCid:508883

153. T. Inoue, M. Yamashita and M. Higaki: 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 20, 149-153 (2001)
doi:10.1007/s002960100104
PMid:11411959

154. T. Nanki, Y. Urasaki, T. Imai, M. Nishimura, K. Muramoto, T. Kubota and N. Miyasaka: Inhibition of fractalkine ameliorates murine collagen-induced arthritis. J Immunol 173, 7010-7016 (2004)

155. J. H. Gong, R. Yan, J. D. Waterfield and I. Clark-Lewis: Post-onset inhibition of murine arthritis using combined chemokine antagonist therapy. Rheumatology (Oxford) 43, 39-42 (2004)
doi:10.1093/rheumatology/keg459
PMid:14566030

156. A. Matsukawa, T. Yoshimura, K. Fujiwara, T. Maeda, S. Ohkawara and M. Yoshinaga: 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 79, 591-600 (1999)

157. P. L. Podolin, B. J. Bolognese, J. J. Foley, D. B. Schmidt, P. T. Buckley, K. L. Widdowson, Q. Jin, J. R. White, J. M. Lee, R. B. Goodman, T. R. Hagen, O. Kajikawa, L. A. Marshall, D. W. Hay and H. M. Sarau: A potent and selective nonpeptide antagonist of CXCR2 inhibits acute and chronic models of arthritis in the rabbit. J Immunol 169, 6435-6444 (2002)

158. M. M. Barsante, T. M. Cunha, M. Allegretti, F. Cattani, F. Policani, C. Bizzarri, W. L. Tafuri, S. Poole, F. Q. Cunha, R. Bertini and M. M. Teixeira: Blockade of the chemokine receptor CXCR2 ameliorates adjuvant-induced arthritis in rats. Br J Pharmacol 153, 992-1002 (2008)
doi:10.1038/sj.bjp.0707462
PMid:17891165    PMCid:2267272

159. T. M. Cunha, M. M. Barsante, A. T. Guerrero, W. A. Verri, Jr., S. H. Ferreira, F. M. Coelho, R. Bertini, C. Di Giacinto, M. Allegretti, F. Q. Cunha and M. M. Teixeira: Treatment with DF 2162, a non-competitive allosteric inhibitor of CXCR1/2, diminishes neutrophil influx and inflammatory hypernociception in mice. Br J Pharmacol 154, 460-470 (2008)
doi:10.1038/bjp.2008.94
PMid:18362895

160. K. Mohan and T. B. Issekutz: Blockade of chemokine receptor CXCR3 inhibits T cell recruitment to inflamed joints and decreases the severity of adjuvant arthritis. J Immunol 179, 8463-8469 (2007)

161. A. Khan, J. Greenman and S. J. Archibald: Small molecule CXCR4 chemokine receptor antagonists: developing drug candidates. Curr Med Chem 14, 2257-2277 (2007)
doi:10.2174/092986707781696618
PMid:17896975

162. S. Hatse, K. Princen, G. Bridger, E. De Clercq and D. Schols: Chemokine receptor inhibition by AMD3100 is strictly confined to CXCR4. FEBS Lett 527, 255-262 (2002)
doi:10.1016/S0014-5793(02)03143-5
PMid:12220670

163. H. Tamamura and N. Fujii: The therapeutic potential of CXCR4 antagonists in the treatment of HIV infection, cancer metastasis and rheumatoid arthritis. Expert Opin Ther Targets 9, 1267-1282 (2005)
doi:10.1517/14728222.9.6.1267
PMid:16300475

164. M. Amat, C. F. Benjamim, L. M. Williams, N. Prats, E. Terricabras, J. Beleta, S. L. Kunkel and N. Godessart: Pharmacological blockade of CCR1 ameliorates murine arthritis and alters cytokine networks in vivo. Br J Pharmacol 149, 666-675 (2006)
doi:10.1038/sj.bjp.0706912
PMid:17016504    PMCid:2014657

165. R. P. Gladue, L. A. Tylaska, W. H. Brissette, P. D. Lira, J. C. Kath, C. S. Poss, M. F. Brown, T. J. Paradis, M. J. Conklyn, K. T. Ogborne, M. A. McGlynn, B. M. Lillie, A. P. DiRico, E. N. Mairs, E. B. McElroy, W. H. Martin, I. A. Stock, R. M. Shepard, H. J. Showell and K. Neote: CP-481,715, a potent and selective CCR1 antagonist with potential therapeutic implications for inflammatory diseases. J Biol Chem 278, 40473-40480 (2003)
doi:10.1074/jbc.M306875200
PMid:12909630

166. J. J. Haringman, M. C. Kraan, T. J. Smeets, K. H. Zwinderman and P. P. Tak: Chemokine blockade and chronic inflammatory disease: proof of concept in patients with rheumatoid arthritis. Ann Rheum Dis 62, 715-721 (2003)
doi:10.1136/ard.62.8.715
PMid:12860725    PMCid:1754636

167. J. E. Pease and R. Horuk: CCR1 antagonists in clinical development. Expert Opin Investig Drugs 14, 785-796 (2005)
doi:10.1517/13543784.14.7.785
PMid:16022568

168. M. P. Quinones, C. A. Estrada, Y. Kalkonde, S. K. Ahuja, W. A. Kuziel, M. Mack and S. S. Ahuja: The complex role of the chemokine receptor CCR2 in collagen-induced arthritis: implications for therapeutic targeting of CCR2 in rheumatoid arthritis. J Mol Med 83, 672-681 (2005)
doi:10.1007/s00109-005-0637-5
PMid:15827759

169. M. P. Quinones, F. Jimenez, H. Martinez, C. A. Estrada, O. Willmon, M. Dudley, W. A. Kuziel, P. C. Melby, R. L. Reddick, S. K. Ahuja and S. S. Ahuja: CC chemokine receptor (CCR)-2 prevents arthritis development following infection by Mycobacterium avium. J Mol Med 84, 503-512 (2006)
doi:10.1007/s00109-006-0039-3
PMid:16520943

170. C. Plater-Zyberk, A. J. Hoogewerf, A. E. Proudfoot, C. A. Power and T. N. Wells: Effect of a CC chemokine receptor antagonist on collagen induced arthritis in DBA/1 mice. Immunol Lett 57, 117-120 (1997)
doi:10.1016/S0165-2478(97)00075-8
PMid:9232436

171. S. Shahrara, A. E. Proudfoot, J. M. Woods, J. H. Ruth, M. A. Amin, C. C. Park, C. S. Haas, R. M. Pope, G. K. Haines, Y. Y. Zha and A. E. Koch: Amelioration of rat adjuvant-induced arthritis by Met-RANTES. Arthritis Rheum 52, 1907-1919 (2005)
doi:10.1002/art.21033

172. H. Bruhl, J. Cihak, J. Plachy, L. Kunz-Schughart, M. Niedermeier, A. Denzel, G. M. Rodriguez, Y. Talke, B. Luckow, M. Stangassinger and M. Mack: Targeting of Gr-1+,CCR2+ monocytes in collagen-induced arthritis. Arthritis Rheum 56, 2975-2985 (2007)
doi:10.1002/art.22854

173. C. A. Bursill, S. Cai, K. M. Channon and D. R. Greaves: Adenoviral-mediated delivery of a viral chemokine binding protein blocks CC-chemokine activity in vitro and in vivo. Immunobiology 207, 187-196 (2003)
doi:10.1078/0171-2985-00228
PMid:12777060

174. J. J. Haringman, D. M. Gerlag, T. J. Smeets, D. Baeten, B. F. van den, B. Bresnihan, F. C. Breedveld, H. J. Dinant, F. Legay, H. Gram, P. Loetscher, R. Schmouder, T. Woodworth and P. P. Tak: A randomized controlled trial with an anti-CCL2 (anti-monocyte chemotactic protein 1) monoclonal antibody in patients with rheumatoid arthritis. Arthritis Rheum 54, 2387-2392 (2006)

175. A. T. Clucas, A. Shah, Y. D. Zhang, V. F. Chow and R. P. Gladue: Phase I evaluation of the safety, pharmacokinetics and pharmacodynamics of CP-481,715. Clin Pharmacokinet 46, 757-766 (2007)
doi:10.2165/00003088-200746090-00003
PMid:17713973

176. N. A. Meanwell and J. F. Kadow: Maraviroc, a chemokine CCR5 receptor antagonist for the treatment of HIV infection and AIDS. Curr Opin Investig Drugs 8, 669-681 (2007)

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

Key Words: Rheumatoid Arthritis, Chemokines, Chemokine Receptors, Targeting, Review