Melanoma susceptibility and progression: Association study between polymorphisms of the chemokine (CCL2) and chemokine receptors (CX3CR1, CCR5).
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Adolescent↗
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Chemokine CCL2 and chemokine receptor CCR2 in early active multiple sclerosis.
The chemokine monocyte chemoattractant protein (MCP)-1/CCL2 and its receptor CCR2 have been strongly implicated in disease pathogenesis in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis (MS), whereas data on the CCL2-CCR2 axis are scarce in MS. We studied the expression of CCR2 on leukocytes in blood and cerebrospinal fluid (CSF) from patients with monosymptomatic optic neuritis and MS, and the concentration of CCL2 in the CSF from these patients. Results were compared with the results in non-inflammatory neurological controls and were correlated with other parameters (magnetic resonance imaging and CSF data). Our findings suggest a limited role for CCL2/CCR2 in early active MS.
Adult↗
Increase of interferon-gamma inducible alpha chemokine CXCL10 but not beta chemokine CCL2 serum levels in chronic autoimmune thyroiditis.
OBJECTIVE: To measure serum levels of CXCL10 and CCL2 prototype chemokines of the two major subclass (CXC and CC) in patients with newly diagnosed chronic autoimmune thyroiditis (AT), and relate the findings to the clinical phenotype. DESIGN AND METHODS: Serum CXCL10 and CCL2 were assayed in 70 consecutive patients with newly diagnosed chronic AT, in sex- and age-matched healthy volunteers (n = 37) and in 20 patients with non-toxic multinodular goiter, extracted from a random sample of the general population from the same geographic area. RESULTS: CXCL10 serum levels were significantly higher in patients with thyroiditis than in controls or multinodular goiter patients, while comparable CCL2 levels were found between groups. CXCL10 levels were significantly increased in hypothyroid patients and in those with an hypoechoic pattern (P = 0.0004 and P = 0.0001, respectively) while serum CCL2 levels were significantly increased in patients older than 50 years and in those with hypothyroidism (P = 0.0001 and P = 0.03, respectively). No correlation between CXCL10 and CCL2 serum levels could be demonstrated. CXCL10 and CCL2 were studied separately in relation to clinical features of AT patients. Two separate multiple linear regression models for CXCL10 and CCL2 were performed, including age, thyroid volume, thyroid stimulating hormone (TSH), FT4, anti-thyroid peroxidase (AbTPO), hypoechoic pattern, and the presence of hypervascularity, demonstrating that ln of serum CXCL10 levels was associated with TSH independently of other possible confounders levels [regression coefficient (R.C.) 0.143 confidence interval (C.I.) (0.042-0.245); P = 0.0059], while serum CCL2 were significantly associated only with age [R.C. 5.412 C.I. (3.838-6.986); P < 0.0001]. CONCLUSION: Our results, obtained in a large cohort of newly diagnosed AT patients demonstrate increased CXCL10 especially in hypothyroid patients with a more aggressive disorder, and normal CCL2 serum levels in AT.
Adult↗
Stem cell factor and igE-stimulated murine mast cells produce chemokines (CCL2, CCL17, CCL22) and express chemokine receptors.
OBJECTIVE AND DESIGN: In the present study we investigated the effect of SCF and/or IgE on histamine, TNF-alpha and chemokines released from bone marrow-derived mast cells (BMMC) as well as chemokine receptor expression. MATERIAL AND METHODS: BMMC were derived from femoral bone marrow of CBA/J mice. The purity of BMMC was >98% after 3 weeks. BMMC (2.5 x 10(6) cells/well) were incubated in the presence or absence of either SCF, IgE plus DNP or a combination of SCF and IgE for 6 and 18 h. Cell-free supernatants were recovered to measure CC chemokines, TNF-alpha and histamine release utilizing ELISA assays. CC chemokine family receptors were detected by RT-PCR analysis, and confirmed using functional chemotactic assays. RESULTS: Histamine levels were comparable between SCF and IgE stimulated cells, whereas TNF-alpha production was significantly greater after IgE compared to SCF stimulation. SCF and/or IgE-stimulated BMMC released CC chemokines, CCL22 (MDC), CCL17 (TARC) and CCL2 (MCP-1). Increased mRNA expression of CCR1, CCR2, CCR3, and CCR5 was detected in SCF and IgE-stimulated BMMCs. Functional chemotactic assays confirmed the expression data. CONCLUSION: SCF and IgE can up-regulate the expression of chemokines and chemokine receptors on mast cells. Thus, SCF may play a significant role in their activation and inflammation during allergic responses.
Animals↗
CCR2-positive monocytes recruited to inflamed lungs downregulate local CCL2 chemokine levels.
The CC chemokine ligand-2 (CCL2) and its receptor CCR2 are essential for monocyte trafficking under inflammatory conditions. However, the mechanisms that determine the intensity and duration of alveolar monocyte accumulation in response to CCL2 gradients in inflamed lungs have not been resolved. To determine the potential role of CCR2-expressing monocytes in regulating alveolar CCL2 levels, we compared leukocyte recruitment kinetics and alveolar CCL2 levels in wild-type and CCR2-deficient mice in response to intratracheal LPS challenge. In wild-type mice, LPS elicited a dose- and time-dependent alveolar monocyte accumulation accompanied by low CCL2 levels in bronchoalveolar lavage fluid (BALF). In contrast, LPS-treated CCR2-deficient mice lacked alveolar monocyte accumulation, which was accompanied by relatively high CCL2 levels in BALF. Similarly, wild-type mice that were treated systemically with the blocking anti-CCR2 antibody MC21 completely lacked LPS-induced alveolar monocyte trafficking that was associated with high CCL2 levels in BALF. Intratracheal application of anti-CCR2 antibody MC21 to locally block CCR2 on both resident and recruited cells did not affect LPS-induced alveolar monocyte trafficking but led to significantly increased BALF CCL2 levels. Reciprocally bone marrow-transplanted, LPS-treated wild-type and CCR2-deficient mice showed a strict inverse relationship between alveolar monocyte recruitment and BALF CCL2 levels. In addition, freshly isolated human and mouse monocytes were capable of integrating CCL2 in vitro. LPS-induced alveolar monocyte accumulation is accompanied by monocytic CCR2-dependent consumption of CCL2 levels in the lung. This feedback loop may limit the intensity of monocyte recruitment to inflamed lungs and play a role in the maintenance of homeostasis.
Animals↗
Effects of the chemokine CCL2 on blood-brain barrier permeability during ischemia-reperfusion injury.
The chemokine CCL2 is considered as one of the main effectors driving postischemic infiltration of monocytes into the brain parenchyma. New experimental data, however, suggest that CCL2 could also participate in blood-brain barrier (BBB) 'opening' during the transmigration of monocytes. The current study examines the role of CCL2 in regulating BBB permeability after ischemia in vitro. To address this issue, an in vitro BBB model (coculture of astrocytes and brain endothelial cells) was subjected to 5 h of oxygen glucose deprivation, followed by reoxgenation (in vitro ischemia/reperfusion (I/R)) for 0 to 48 h. During reperfusion, there was a biphasic enhancement of barrier permeability, with a 200-fold increase in barrier permeability to FITC-albumin at 6 h and a further period of disruption around 24 h. The latter coincided with increased secretion of CCL2 by both astrocytes and brain endothelial cells and increased levels of the CCL2 receptor, CCR2. Applying antisense oligonucleotide or neutralizing antibody to block CCL2 significantly decreased I/R-induced enhancement of BBB permeability (approximately twofold) and redistribution of tight-junction (TJ) proteins (occludin, zonula occluden-1, 2, claudin-5). Similarly, absence of CCR2 from endothelial cells caused stabilization of TJ complexes and decreased the permeability of brain endothelial barrier during in vitro I/R. These data suggest CCL2/CCR2 has an important role in regulating brain endothelial permeability and might be a potential novel therapeutic target for stroke.
Animals↗
The chemokine CCL2 modulates Ca2+ dynamics and electrophysiological properties of cultured cerebellar Purkinje neurons.
The chemokine CCL2 is produced at high levels in the central nervous system (CNS) during infection, injury, neuroinflammation and other pathological conditions. Cells of the CNS including neurons and glia express receptors for CCL2 and these receptors may contribute to a signaling system through which pathologic conditions in the CNS are communicated. However, our understanding of the consequences of activation of chemokine signaling in the CNS is limited, especially for neurons. In many cell types, chemokine signaling alters intracellular Ca(2+) dynamics. Therefore, we investigated the potential involvement of this mechanism in neuronal signaling activated by CCL2. In addition, we examined the effects of CCL2 on neuronal excitability. The studies focused on the rat cerebellar Purkinje neuron, an identified CNS neuronal type reported to express both CCL2 and its receptor, CCR2. Immunohistochemical studies of Purkinje neurons in situ confirmed that they express CCR2 and CCL2. The effect of exogenous application on Purkinje neurons was studied in a cerebellar culture preparation. CCL2 was tested by micropressure or bath application, at high concentrations (13-100 nm) to simulate conditions during a pathologic state. Results show that Purkinje neurons express receptors for CCL2 and that activation of these receptors alters several neuronal properties. CCL2 increased resting Ca(2+) levels, enhanced the Ca(2+) response evoked by activation of metabotropic glutamate receptor 1 and depressed action potential generation in the cultured Purkinje neurons. Passive membrane properties were unaltered. These modulatory effects of CCL2 on neuronal properties are likely to contribute to the altered CNS function associated with CNS disease and injury.
Action Potentials↗
Constitutive secretion of the granule chymase mouse mast cell protease-1 and the chemokine, CCL2, by mucosal mast cell homologues.
BACKGROUND: The mucosal mast cell (MMC) granule-specific beta-chymase, mouse mast cell protease-1 (mMCP-1), is released systemically into the bloodstream early in nematode infection before parasite-specific IgE responses develop and TGF-beta1 induces constitutive release of mMCP-1 by homologues of MMC in vitro. Intraepithelial MMC may also express the chemokine CCL2 (monocyte chemotactic protein-1) during nematode infection but the expression of this chemokine by MMC homologues has not been investigated. OBJECTIVE: To investigate the expression and to compare the mechanisms of constitutive release of the chymase, mMCP-1, and the chemokine, CCL2. METHODS: MMC homologues were generated by culturing bone marrow cells in the presence of TGF-beta1, IL-3, IL-9 and stem cell factor (SCF). The intracellular distribution of mMCP-1 and CCL2 was examined by confocal microscopy. The involvement of the Golgi complex and of protein synthesis in the constitutive release of mMCP-1 and CCL2 was investigated using the Golgi-disrupting agent brefeldin A and cycloheximide to block protein synthesis. Secreted analytes were quantified by ELISA. RESULTS: mMCP-1 colocalized with Golgi matrix protein 130 but was most abundant in the granules, whereas CCL2 was not found in the granules but appeared to be located uniquely in the Golgi complex. Extracellular release of mMCP-1 was significantly inhibited ( approximately 40%) by cycloheximide and by the Golgi-disrupting agent brefeldin A, indicating both continuous protein synthesis and transportation via the Golgi complex are required for optimal mMCP-1 secretion. A similar but more marked inhibitory effect with both compounds was demonstrated on the constitutive secretion of CCL2. CONCLUSION: The culture conditions that promote mMCP-1 expression and release by MMC homologues also promote the expression and release of CCL2. Constitutive release involves de novo protein synthesis and requires a functional Golgi complex, suggesting that similar mechanisms of extracellular secretion operate for both mediators.
Animals↗
The chemokine CCL2 is required for control of murine gastric Salmonella enterica infection.
Salmonella enterica is a gram-negative intracellular pathogen that can cause a variety of diseases ranging from gastroenteritis to typhoid fever. The Typhimurium serotype causes gastroenteritis in humans; however, infection of mice results in an enteric fever that resembles human typhoid fever and has been used as a model for typhoid fever. The present study examined the role of the chemokine CCL2 in the control of Salmonella infection. Upon infection with salmonellae, mucosal expression of CCL2 is rapidly up-regulated, followed by systemic expression in the spleen. CCL2(-/-) mice became moribund earlier and had a higher rate of mortality compared to wild-type C57BL/6 mice. Moreover, CCL2(-/-) mice had significantly higher levels of bacteria in the liver compared to wild-type controls. Mucosal and serum interleukin-6 and tumor necrosis factor alpha levels were elevated in CCL2(-/-) mice compared to wild-type mice. In vitro analysis demonstrated that CCL2(-/-) macrophages infected with salmonellae resulted in dysregulated cytokine production compared to macrophages derived from wild-type mice. These data are the first to directly demonstrate CCL2 as a critical factor for immune responses and survival following S. enterica infection.
Animals↗
Increase of CXC chemokine CXCL10 and CC chemokine CCL2 serum levels in normal ageing.
No study has evaluated contemporaneously serum CXC and CC chemokines changes in normal ageing. Serum levels of CXCL10 (sCXCL10) (CXC) and CCL2 (sCCL2) (CC) prototype chemokines have been measured in 164 healthy subjects, from 10 to 79 years of age (82 males/82 females). By simple regression analysis, sCXCL10 and sCCL2 were significantly related with increasing age (r=0.32, p<0.001; r=0.31, p<0.0001, respectively), and with each other (r=0.30, p=0.0004). In a multiple linear regression model, only age and sCCL2 were significantly related to sCXCL10 levels (p<0.001); age and sCXCL10 were significantly related to sCCL2 levels (p<0.001). Subjects with high sCXCL10 levels (>150 pg/ml) were not significantly associated with those with high sCCL2 levels (>559 pg/ml). This study, performed in healthy subjects on an age gradient, demonstrates an increase of sCXCL10 and sCCL2 with advancing age; the differential increase of sCXCL10 or sCCL2 may reflect a general shift towards Th1 or Th2 cytokines pattern, respectively.
Adolescent↗
Natural killer T cells infiltrate neuroblastomas expressing the chemokine CCL2.
CD1d-restricted Valpha24-Jalpha18-invariant natural killer T cells (iNKTs) are potentially important in tumor immunity. However, little is known about their localization to tumors. We analyzed 98 untreated primary neuroblastomas from patients with metastatic disease (stage 4) for tumor-infiltrating iNKTs using TaqMan((R)) reverse transcription polymerase chain reaction and immunofluorescent microscopy. 52 tumors (53%) contained iNKTs, and oligonucleotide microarray analysis of the iNKT(+) and iNKT(-) tumors revealed that the former expressed higher levels of CCL2/MCP-1, CXCL12/SDF-1, CCL5/RANTES, and CCL21/SLC. Eight tested neuroblastoma cell lines secreted a range of CCL2 (0-21.6 ng/ml), little CXCL12 (</=0.1 ng/ml), and no detectable CCL5 or CCL21. CCR2, the receptor for CCL2, was more frequently expressed by iNKT compared with natural killer and T cells from blood (P < 0.001). Supernatants of neuroblastoma cell lines that produced CCL2 induced in vitro migration of iNKTs from blood of patients and normal adults; this was abrogated by an anti-CCL2 monoclonal antibody. CCL2 expression by tumors was found to inversely correlate with MYCN proto-oncogene amplification and expression (r = 0.5, P < 0.001), and MYCN-high/CCL2-low expression accurately predicted the absence of iNKTs (P < 0.001). In summary, iNKTs migrate toward neuroblastoma cells in a CCL2-dependent manner, preferentially infiltrating MYCN nonamplified tumors that express CCL2.
Antineoplastic Combined Chemotherapy Protocols↗
Metalloproteinases control brain inflammation induced by pertussis toxin in mice overexpressing the chemokine CCL2 in the central nervous system.
Inflammatory leukocytes infiltrate the CNS parenchyma in neuroinflammation. This involves cellular migration across various structures associated with the blood-brain barrier: the vascular endothelium, the glia limitans, and the perivascular space between them. Leukocytes accumulate spontaneously in the perivascular space in brains of transgenic (Tg) mice that overexpress CCL2 under control of a CNS-specific promoter. The Tg mice show no clinical symptoms, even though leukocytes have crossed the endothelial basement membrane. Pertussis toxin (PTx) given i.p. induced encephalopathy and weight loss in Tg mice. We used flow cytometry, ultra-small superparamagnetic iron oxide-enhanced magnetic resonance imaging, and immunofluorescent staining to show that encephalopathy involved leukocyte migration across the glia limitans into the brain parenchyma, identifying this as the critical step in inducing clinical symptoms. Metalloproteinase (MPs) enzymes are implicated in leukocyte infiltration in neuroinflammation. Unmanipulated Tg mice had elevated expression of tissue inhibitor of metalloproteinase-1, matrix metalloproteinase (MMP)-10, and -12 mRNA in the brain. PTx further induced expression of tissue inhibitor of metalloproteinase-1, metalloproteinase disintegrins-12, MMP-8, and -10 in brains of Tg mice. Levels of the microglial-associated MP MMP-15 were not affected in control or PTx-treated Tg mice. PTx also up-regulated expression of proinflammatory cytokines IL-1beta and TNF-alpha mRNA in Tg CNS. Weight loss and parenchymal infiltration, but not perivascular accumulation, were significantly inhibited by the broad-spectrum MP inhibitor BB-94/Batimastat. Our finding that MPs mediate PTx-induced parenchymal infiltration to the chemokine-overexpressing CNS has relevance for the pathogenesis of human diseases involving CNS inflammation, such as multiple sclerosis.
Animals↗
Serial measurements of levels of the chemokines CCL2, CCL3 and CCL5 in serum of patients with acute ischaemic stroke.
Inflammation, involving cytokine/chemokine expression, occurs after stroke and deteriorates its course with leukocyte-mediated brain infarct progression. Chemokines are cytokines attracting selective leukocyte subsets and subgrouping into the four major subfamilies, CC, CXC, C, and CX3C. The CC subfamily preferentially acts on mononuclears. The study aimed to define serum CCL2, CCL3 and CCL5 levels in stroke patients and their relationship to the extent of disease severity and outcome. 27 ischaemic stroke patients and 20 controls were studied. Blood sampling for the determination of chemokines was performed at days 1, 2 and 3 of stroke, while neurological and functional deficits were estimated, respectively, with the Scandinavian Stroke Scale (SSS) and Barthel Index (BI) at the same time points and at days 14 and 28. Serum CCL3 levels at days 1, 2 and 3 of stroke were significantly higher than in controls. Serum CCL2 and CCL5 levels in stroke patients did not differ from those in controls at any of the time points examined. Serum chemokine levels in stroke studied separately did not differ between each other at any time point studied and demonstrated considerable variability. No correlation between serum chemokine levels and SSS scores was observed. Serum CCL2 and CCL3 levels at days 1, 2 and 3 of stroke correlated with BI scores at day 28. Serum CCL2 levels at days 2 and 3 of stroke also correlated with BI scores at day 14. Serum CCL5 levels at day 2 of stroke correlated with BI scores at day 28. The early and sustained increase in serum CCL3 levels in stroke patients along with correlation between them and short-term poststroke functional disability could indicate that the chemokine response may predispose to poor stroke outcome. The relationship between non-increased serum CCL2 and CCL5 levels and worse stroke outcome seems to be coincidental. Overall, as a result of large interindividual variability, CCL2, CCL3 and CCL5 are not reliable candidates for surrogate markers in stroke.
Aged↗
Effect of the treatment with methylprednisolone on the cerebrospinal fluid and serum levels of CCL2 and CXCL10 chemokines in patients with active multiple sclerosis.
BACKGROUND: Several experimental and human studies suggest that the chemokines CCL2 and CXCL10 may play a role in the pathogenesis of multiple sclerosis (MS). Here, we evaluated the effect of intravenous methylprednisolone (IVMP) therapy on the levels of CCL2 and CXCL10 in the cerebrospinal fluid (CSF) and serum of patients with active MS. METHODS: Serum and CSF samples were obtained from 14 patients with active relapsing-remitting MS (age +/- SD years, 37.0 +/- 8.1; M/F, 6/8) and age- and gender-matched control subjects. All patients were submitted to IVMP treatment (500 mg daily for 5 days). Blood and CSF sampling were performed at admission, i.e. before treatment (day 0), at the end of the treatment (day 6) and 30 days after treatment (day 30). The clinical status of MS patients was also assessed. CCL2 and CXCL10 were measured by enzyme-linked immunosorbent assay. RESULTS: Multiple sclerosis patients had lower CCL2 and higher CXCL10 in CSF when compared with control subjetcs. After treatment with methylprednisolone, MS patients showed clinical improvement and the CSF concentrations of CCL2 and CXCL10 modified toward normal values. CONCLUSIONS: The clinical improvement of active MS following the treatment with methylprednisolone was associated with the modification of CSF levels of CCL2 and CXCL10, suggesting that these chemokines may be useful markers of response to treatment and relapses in MS patients.
Adult↗
The levels of chemokines CXCL8, CCL2 and CCL5 in multiple sclerosis patients are linked to the activity of the disease.
Chemokines are small cytokines with selective chemoattractant properties. They contribute to the T-cell-mediated pathogenesis of multiple sclerosis (MS). In order to ascertain whether different types and stage of disease correlate with a varying level of chemokines, the levels of CXCL8, CCL2 and CCL5 were measured in serum and the cerebrospinal fluid (CSF) of the MS patients. ELISA method was used to examine 56 patients with different types of MS alongside the 29 patients of the control group. The levels of CXCL8 and CCL2 in both groups were higher in CFS than in serum whilst the level of CCL5 measured higher in serum than in CSF. A significant rise in the levels of CXCL8 and CCL5 was observed during relapse, as against the level of CCL2 which was lower when compared with the control and other MS groups. No significant differences were observed in the levels of chemokines between the stable relapsing-remitting MS and progressive MS. The different levels of chemokines are linked to relapse of the disease. No separate, specific pattern of chemokine production dependent on the type of MS could be ascertained.
Adult↗
Glycosylation enhances functional stability of the chemotactic cytokine CCL2.
The human chemokine CCL2 gene was expressed in the yeast P.pastoris and gave rise to a mixture of differently glycosylated recombinant proteins. In comparison to non-glycosylated E.coli-derived CCL2, glycosylated yeast CCL2L was 4-20 times less active in a chemotactic assay in vitro. However, CCL2L could maintain full activity upon prolonged incubation at 37 degrees C, whereas the non-glycosylated chemokine readily lost activity. It could be hypothesized that glycosylation is a mechanism used by the organism to modulate CCL2 stability. The partial loss of specific activity due to glycosylation is balanced by the advantage of prolonging the effectiveness of chemokine. Thus, differential glycosylation allows one to obtain highly effective short-lived CCL2 or less-effective long-lived CCL2 and may thus represent a novel mechanism of adaptation to pathological versus physiological conditions.
Chemokines↗
CCR2 expression by brain microvascular endothelial cells is critical for macrophage transendothelial migration in response to CCL2.
While the expression of chemokine receptors by endothelial cells is now well established, little is known of the function of these receptors at this cellular locale. However, given that chemokines are instrumental in directing leukocytes to specific parenchymal sites, one possibility is that endothelial chemokine receptors play a role in the process of leukocyte extravasation. To test this hypothesis, we investigated the contribution of CCR2, the major cognate receptor for the chemokine CCL2 (formerly known as MCP-1), to CCL2-stimulated transendothelial migration of macrophages (mØ) across cultured brain microvascular endothelial cells (BMEC). Specifically, we prepared both BMEC and mØ from wild-type (WT) mice and mice deficient in CCR2; i.e., CCR2 (-/-), and compared the ability of WT and CCR2 (-/-) BMEC to support CCL2-stimulated transendothelial migration of WT and CCR2 (-/-) mØ. In response to CCL2, WT mØ, but not CCR2 (-/-) mØ, were stimulated to migrate across WT BMEC, consistent with the recognized obligatory role for CCR2 in mediating CCL2-stimulated responses. Remarkably, however, neither WT nor CCR2 (-/-) mØ were stimulated by CCL2 to migrate across CCR2 (-/-) BMEC. In contrast, both types of mØ were able to migrate similarly across both types of BMEC in response to another chemokine--CCL3 (formerly known as MIP-1alpha)--which utilizes receptors other than CCR2. Lastly, CCL2-induced mØ transendothelial migration was blocked by treatment of WT BMEC with pertussis toxin, suggesting that CCR2 is functionally coupled to the inhibitory G protein Galphai, much as it is in other cell types. These results highlight a heretofore-unrecognized role for endothelial CCR2 in mediating transendothelial migration.
Animals↗
The chemokines CCL5, CCL2 and CXCL12 play significant roles in the migration of Th1 cells into rheumatoid synovial tissue.
As the T-cell population in the synovial tissue (ST) in rheumatoid arthritis (RA) is dominated by T helper (Th) 1 cells, this study was designed to examine whether there is a preferential migration of polarized T cells to ST, and to identify the chemokines responsible for the migration. This was done by developing 10 T-cell clones specific for an arbitrary antigen (mouse immunoglobulin G (IgG)) from the peripheral blood (PB) of a healthy donor sensitized to mouse IgG. The Th polarizations of the clones were determined by measuring secreted interferon-gamma and interleukin-4, following anti-CD3 stimulation. Migration to pools of RA ST cell-derived supernatants was analysed. Expression of the chemokine receptors CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CXCR3 and CXCR4 were analysed by flow cytometry. Th1 clones showed significantly higher migration to RA ST cell-derived supernatant compared with Th2 clones. Blocking of either of the chemokines, CCL5 or CCL2, strongly inhibited migration of the Th1 cells between 56 and 77%, while blocking of CXCL12 inhibited migration between 44 and 61%. Blocking of CXCL10 had only a minor inhibitory effect. Our results demonstrate a selective migration of Th1 cells to RA ST supernatant and that blocking either CCL5, CCL2 or CXCL12 significantly inhibits T-cell migration. This indicates that CCL5, CCL2 and CXCL12 play significant roles in attracting Th1 cells towards the RA ST, and may prove potent targets for obstructing T-cell migration to the synovium.
Arthritis, Rheumatoid↗