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PubMed2004

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↗
PubMed2004

Steroid therapy altered serum levels of CCL2 and CCL5 chemokines in multiple sclerosis patients during relapse.

Chemokines are involved in the pathogenesis of multiple sclerosis. The aim of this study was to determine the impact of steroid therapy on the levels of CCL2 and CCL5 chemokines. The study encompassed 30 patients with clinically definite relapsing-remitting multiple sclerosis who were treated with methylprednisolone due to the relapse of the disease. The control groups consisted of 20 patients during the stable stage of relapsing-remitting multiple sclerosis and of 15 patients with noninflammatory diseases of the nervous system. Both chemokines were markedly expresssed in serum by enzyme-linked immunosorbent assay. During relapse, the levels of both chemokines differed significantly from the levels measured in both control groups. After the methylprednisolone treatment, the chemokine levels changed significantly: the levels of CCL2 increased, whilst the levels of CCL5 decreased. These alterations did not correlate with the clinical state of the patients or with the therapeutic effect of the treatment and indicated that the inflammatory reaction accompanying the relapse was receding.

Adult↗
PubMedDate not supplied

IL-10 enhances CCL2 release and chemotaxis induced by CCL16 in human monocytes.

CCL16 is a CC chemokine originally identified as a liver-expressed chemokine. Its expression has been detected in activated monocytes where it is up-regulated by stimulation with IL-10. This is in contrast with IL-10's inhibition of the expression of most chemokines. CCL16 is chemotactic for monocytes, lymphocyte and dendritic cells. We investigated whether CCL16 displays biological activities other than chemotaxis and whether IL-10 affects monocyte response to CCL16. We show that CCL16 induces the expression of CCL2 at the mRNA and protein level, but does not affect that of CCL5, CCL18 and proinflammatory cytokines. This effect was prevented by treatment with pertussis toxin and may thus be mediated by G-protein-coupled receptors. IL-10 markedly increased CCL2 production induced by CCL16, but suppressed that of CXCL8. It also enhanced the chemotactic response to CCL16. Addition of antibodies blocking CCR1, but not CCR8, prevented this enhanced chemotactic response and suggested that CCR1 is primarily involved. We propose that IL-10 modulates the effects of CCL16 on monocytes by increasing their CCR1-dependent response. The coordinated secretion of CCL16 and IL-10 may thus enhance monocyte infiltration.

Cell Line↗
PubMed2003

Monocytes are potent facilitators of alveolar neutrophil emigration during lung inflammation: role of the CCL2-CCR2 axis.

Coordinated neutrophil and monocyte recruitment is a characteristic feature of acute lung inflammatory responses. We investigated the role of monocyte chemotactic protein-1 (CCL2, JE) and the chemokine receptor CCR2 in regulating alveolar leukocyte traffic. Groups of wild-type (WT) mice, CCR2-deficient mice, lethally irradiated CCR2-deficient and WT mice that were reciprocally bone marrow transplanted (chimeric CCR2 deficient and WT, respectively), chimeric CCR2-deficient mice with an enriched CCR2(+) alveolar macrophage population, and CCR2-deficient mice transfused with CCR2(+) mononuclear cells were treated with intratracheal CCL2 and/or Escherichia coli endotoxin. Our data show that alveolar monocyte recruitment is strictly dependent on CCR2. LPS-induced neutrophil migration to the lungs is CCR2 independent. However, when CCR2-bearing blood monocytes are present, alveolar neutrophil accumulation is accelerated and drastically amplified. We suggest that this hitherto unrecognized cooperativity between monocytes and neutrophils contributes to the strong, coordinated leukocyte efflux in lung inflammation.

Adoptive Transfer↗
PubMed2005

Interleukin-32, CCL2, PF4F1 and GFD10 are the only cytokine/chemokine genes differentially expressed by in vitro cultured rheumatoid and osteoarthritis fibroblast-like synoviocytes.

Since cytokines and chemokines are important actors in rheumatoid arthritis (RA), the aim of this study was to compare the gene expression profiles in cultured fibroblast-like synoviocytes (FLS) obtained from patients with either RA, or osteoarthritis (OA), focusing our analysis on genes for cytokines and chemokines, and their respective receptors. Gene expression in cultured FLS (third passage) from eight patients with RA (RA-FLS) were compared with gene expression in cultured FLS from nine patients with OA (OA-FLS) using Affymetrix Human Genome U133 Plus 2.0 Array microarray, allowing analysis of over 54,000 transcripts. Among the 171 genes studied (241 probes), limiting the selection of differentially expressed genes to a significant value (p < 0.05), and a differential ratio of expression > 1.6, only four genes, namely IL-32, CCL2, PF4F1 and GDF10 were found to be differentially expressed. Out of these four genes, only higher expression of CCL2 has been reported previously in RA. The newly described cytokine IL-32 was the most prominently differentially expressed gene in the present study, with higher expression in RA-FLS than in OA-FLS (p < 0.0073). IL-32 might have a previously unidentified pivotal role in RA.

Arthritis, Rheumatoid↗
PubMed2003

Expression of L-CCR in HEK 293 cells reveals functional responses to CCL2, CCL5, CCL7, and CCL8.

It has become clear in the past years that chemokines and chemokine receptors are pivotal regulators of cellular communication and trafficking. In addition to the approximately 20 chemokine receptors that have been cloned and described, various orphan receptors with a chemokine receptor-like structure are known. We have investigated the orphan mouse chemokine receptor (L-CCR) in HEK 293 cells, a receptor that was originally described in a mouse macrophage cell line. Cells expressing this receptor show pertussis toxin-sensitive chemotaxis and small intracellular calcium transients in response to the chemokines CCL2, CCL7, CCL8, and CCL5. Biotinylated CCL2 binds to L-CCR-expressing cells, and transfection experiments with an L-CCR-green fluorescent protein fusion protein showed L-CCR expression in the membranes of recombinant HEK 293 cells. Although radioligand binding was not detected, it is suggested that L-CCR is a functional chemokine receptor.

Actins↗
PubMed2006

A randomized controlled trial with an anti-CCL2 (anti-monocyte chemotactic protein 1) monoclonal antibody in patients with rheumatoid arthritis.

OBJECTIVE: Chemokines such as CCL2/monocyte chemotactic protein 1 (MCP-1) play a key role in leukocyte migration and are potential targets in the treatment of chronic inflammatory disorders. The objective of this study was to evaluate the effects of human anti-CCL2/MCP-1 monoclonal antibody (ABN912) treatment in patients with rheumatoid arthritis (RA). METHODS: Patients with active RA were enrolled in a randomized, placebo-controlled, dose-escalation study of ABN912. Infusions were administered on day 1 and day 15. In the dose-escalation phase, 4 cohorts of 8 patients each underwent serial arthroscopic biopsy of synovial tissue. Immunohistochemistry and digital image analysis were used to characterize biomarkers in synovial tissue. Laboratory evaluation included pharmacokinetic analysis and immunotypic studies of peripheral blood mononuclear cells. To assess the clinical effects of treatment with ABN912, an additional 21 patients were treated with the highest dose tolerated. RESULTS: The total study population comprised 45 patients: 33 patients received ABN912, and 12 patients received placebo. ABN912 treatment was well tolerated. Unexpectedly, there was a dose-related increase in ABN912-complexed total CCL2/MCP-1 levels in peripheral blood, up to 2,000-fold. There was no detectable clinical benefit of ABN912 compared with placebo, nor did treatment with the study drug result in a significant change in the levels of biomarkers in synovial tissue and peripheral blood. CONCLUSION: ABN912 treatment did not result in clinical or immunohistologic improvement and may have been associated with worsening of RA in patients treated with the highest dose. The results might be related to the greatly increased level of total CCL2/MCP-1 in serum that was observed following treatment with ABN912. This observation may be relevant for a variety of antibody-based therapies.

Adult↗
PubMed2004

Correlations between IL-4, IL-12 levels and CCL2, CCL5 levels in serum and cerebrospinal fluid of multiple sclerosis patients.

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS). Both cytokines and chemokines have been implicated in the pathogenesis of MS. The aim of the study was to assess whether cytokine levels are correlated with chemokine levels during a different stage of relapsing-remitting MS (RR-MS). The study included 53 patients with RR-MS (20 subjects in stable stage and 18 patients with relapse). By ELISA method, the levels of the interleukin-4 (IL-4), interleukin-12 (IL-12), CCL2 and CCL-5 chemokines were measured both in serum and cerebrospinal fluid (CSF) of all patients. The serum IL-4 and IL-12 levels and CSF CCL5 level of patients with stable RR-MS were significantly different from the control level and the IL-12 levels were correlated with CCL5 levels in serum. During the relapse, a significant change in chemokine levels both in serum and CSF and IL-12 in CSF were noted, however no correlations were found between cytokines and chemokines.

Adult↗
PubMed2006

CCL2 (Monocyte Chemoattractant Protein-1) in cancer bone metastases.

The paradigm of cancer development and metastasis is a comprehensive, complex series of events that ultimately reflects a coordinated interaction between the tumor cell and the microenvironment within which the tumor cell resides. Despite the realization that this relationship has changed the current paradigm of cancer research, the struggle continues to more completely understand the pathogenesis of the disease and the ability to appropriately identify and design novel targets for therapy. A particular area of research that has added a significant understanding to cancer metastasis is the role of chemokines and chemokine receptors. Here we review the current concepts of CCL2 (monocyte chemoattractant protein 1) and its role in tumor metastasis with particular interest to its role in the development of bone metastases.

Animals↗
PubMed2006

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↗
PubMed2003

U50,488 inhibits HIV-1 Tat-induced monocyte chemoattractant protein-1 (CCL2) production by human astrocytes.

Kappa-opioid receptor (KOR) ligands have been reported to alter many cell functions and to exert an immunomodulatory role in the CNS. Astrocytes, the predominant brain cell type, have been implicated in the neuropathogenesis of human immunodeficiency virus type 1 (HIV-1). HIV-1 nuclear protein Tat has been reported to induce production of the chemokine monocyte chemoattractant protein-1 (MCP-1 or CCL2) and to activate nuclear factor kappaB (NF-kappaB) in human astrocytes. In the present study, we investigated whether the synthetic KOR ligand trans-3,4-dichloro-N-methyl-N[2-(1-pyrolidinyl)cyclohexyl]benzeneacetamide methanesulfonate (U50,488) would down-regulate MCP-1 production in primary human astrocytes stimulated by Tat. Treatment of astrocytes with U50,488 inhibited Tat-induced MCP-1 production in a concentration-dependent manner. The KOR-selective antagonist nor-binaltrophimine (nor-BNI) completely blocked the inhibitory effect of U50,488, indicating involvement of KOR. While U50,488 alone had a partial inhibitory effect on constituent NF-kappaB activation, it potently suppressed Tat-induced NF-kappaB activation. These findings suggest that KOR ligands could have an anti-inflammatory effect in the CNS and thereby be beneficial in the treatment of HIV-1-associated brain disease.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed2004

Examination of MCP-1 (CCL2) partitioning and presentation during transendothelial leukocyte migration.

It is proposed that a chemokine concentration gradient promotes vectorial leukocyte migration across the vascular endothelium during inflammation. In this study, monocyte migration across a model endothelial monolayer was assessed at defined time-points after the addition of MCP-1 (CCL2). At each time-point transendothelial migration was quantified, medium from the apical and basal surface was collected for ELISA and monolayers were stained to detect both heparan sulfate and MCP-1. Statistically significant monocyte migration was observed within 60 min of chemokine addition to the basal surface of the endothelium and an asymmetric distribution of MCP-1 across the monolayer was observed at all time-points. Dual color immunofluorescence analysis demonstrated that MCP-1 was focused into heparan sulfate-containing domains on the apical surface of some of the endothelial cells. Furthermore, no uniform concentration gradient of chemokine was observed within the space between adjacent endothelial cells with apical MCP-1 application resulting in a staining pattern identical to that observed after basal application. The addition of a functional, monomeric form of MCP-1 produced a staining pattern identical to that observed using the wild-type protein, suggesting that localized chemokine oligomerization is not responsible for generating the focal chemokine distribution. Together, these data suggest that apical presentation of concentrated, chemokine-containing domains provides sufficient stimulus to promote transendothelial leukocyte migration in the absence of the formation of a formal haptotactic concentration gradient between endothelial cells.

Binding Sites↗
PubMed2003

Monocyte chemoattractant protein-1 (CCL2) in inflammatory disease and adaptive immunity: therapeutic opportunities and controversies.

Monocyte chemoattractant protein (MCP)-1 (CCL2) specifically attracts monocytes and memory T cells. Its expression occurs in a variety of diseases characterized by mononuclear cell infiltration, and there is substantial biological and genetic evidence for its essential role in atherosclerosis and multiple sclerosis. Despite intensive screening, there are as yet no small-molecule antagonists of the receptor of MCP-1/CCL2, CCR2. However, biological agents, including antibodies and inhibitory peptides, have been developed and may be useful for these indications. Recent evidence from genetically modified mice indicates that MCP-1 and CCR2 have unanticipated effects on T helper (Th) cell development. However, unlike the identical phenotypes of MCP-1/CCL2(-/-) and CCR2(-/-) mice in inflammatory diseases, the phenotypes of these mice are disparate in adaptive immunity: MCP-1 stimulates Th2 polarization, whereas CCR2 activation stimulates Th1 polarization. This presents both a challenge and an opportunity for targeting the MCP-1/CCL2/CCR2 axis in disease.

Adaptation, Physiological↗
PubMed2003

MCP-1 (CCL2) protects human neurons and astrocytes from NMDA or HIV-tat-induced apoptosis.

Acquired immunodeficiency syndrome (AIDS)-associated dementia is often characterized by chronic inflammation, with infected macrophage infiltration of the CNS resulting in the production of human immunodeficiency virus type 1 (HIV-1) products, including tat, and neurotoxins that contribute to neuronal loss. In addition to their established role in leukocyte recruitment and activation, we identified an additional role for chemokines in the CNS. Monocyte chemoattractant protein-1 (MCP-1 or CCL2) and regulated upon activation normal T cell expressed and secreted (RANTES) were found to protect mixed cultures of human neurons and astrocytes from tat or NMDA-induced apoptosis. Neuronal and astrocytic apoptosis in these cultures was significantly inhibited by co-treatment with MCP-1 or RANTES but not IP-10. The protective effect of RANTES was blocked by antibodies to MCP-1, indicating that RANTES protection is mediated by the induction of MCP-1. The NMDA blocker, MK801, also abolished the toxic effects of both tat and NMDA. Tat or NMDA treatment of mixed cultures for 24 h resulted in increased extracellular glutamate ([Glu]e) and NMDA receptor 1 (NMDAR1) expression, potential contributors to apoptosis. Co-treatment with MCP-1 inhibited tat and NMDA-induced increases in [Glu]e and NMDAR1, and also reduced the levels and number of neurons containing intracellular tat. These data indicate that MCP-1 may play a novel role as a protective agent against the toxic effects of glutamate and tat.

AIDS Dementia Complex↗
PubMed2005

Viral expression of CCL2 is sufficient to induce demyelination in RAG1-/- mice infected with a neurotropic coronavirus.

Mouse hepatitis virus strain JHM causes a chronic demyelinating disease in susceptible strains of rodents. Demyelination does not develop in infected RAG1-/- (recombination activation gene-deficient) mice but can be induced by several experimental interventions, including adoptive transfer of virus-specific T cells or antibodies. A common feature of demyelination in these models is extensive infiltration of macrophages/microglia into the white matter. The data obtained thus far do not indicate whether macrophage/microglia infiltration, in the absence of T cells or antibody, is sufficient to mediate demyelination. To determine whether the expression of a single macrophage chemoattractant, in the context of virus infection, could initiate the demyelinating process, we engineered a recombinant coronavirus that expressed the chemokine CCL2/monocyte chemoattractant protein-1. CCL2 has been implicated in macrophage infiltration into the central nervous system and is involved in demyelination in many experimental models of demyelination. Extensive macrophage/microglia infiltration and demyelination has developed in RAG1-/- mice infected with this recombinant virus. Thus, these results suggest that the minimal requirement for demyelination is increased expression of a single macrophage-attracting chemokine in the context of an inflammatory milieu, such as that induced by a viral infection.

Animals↗
PubMed2004

Crucial role of the CCL2/CCR2 axis in neointimal hyperplasia after arterial injury in hyperlipidemic mice involves early monocyte recruitment and CCL2 presentation on platelets.

Monocyte chemoattractant protein-1 (also known as CC chemokine ligand 2 [CCL2]) and its receptor CC chemokine receptor 2 (CCR2) play a central role in the inflammatory response and neointimal formation after vascular injury. In the context of hyperlipidemia, this appears to involve neointimal monocyte infiltration. Hence, we investigated the function of the CCL2/CCR2 axis in early monocyte recruitment to injured arteries. Wire-induced injury of the carotid artery in apoE-/- mice caused a rapid increase of JE/CCL2 protein in the vessel wall peaking at 24 hours after injury, whereas serum JE/CCL2 was increased solely at 6 hours and blood cell-associated levels were unaltered, as demonstrated by enzyme-linked immunosorbent assay. Immunohistochemistry revealed intense staining for JE/CCL2 in smooth muscle cells (SMCs) and in association with platelets adherent to the denuded vessel wall 24 hours after injury. In vitro, exogenous or SMC-derived JE/CCL2 binds to the platelet surface and triggers monocyte arrest on adherent platelets but not on SMCs in flow assays. Accordingly, monocyte arrest in ex vivo perfused apoE-/- carotid arteries isolated 24 hours after injury was profoundly inhibited by pretreatment with a JE/CCL2 antibody. In CCR2-/-/apoE-/- mice, neointimal plaque area was reduced by 47% compared with CCR2+/+/apoE-/- mice. Moreover, CCR2 deletion markedly decreased neointimal macrophage content while expanding SMC content. Vascular JE/CCL2 expressed by SMCs and immobilized by adherent platelets after endothelial denudation is crucial for mediating early monocyte recruitment to injured arteries in hyperlipidemic mice. This mechanism may explain reduced neointimal macrophage infiltration and lesion formation in CCR2-deficient apoE-/- mice.

Animals↗
PubMed2006

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↗
PubMed2001

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↗