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PubMed2000

Syntheses and 1H-, 13C- and 15N-NMR spectra of ethynyl isocyanide, H-C triple bond C-N triple bond C, D-C triple bond C-N triple bond C and prop-1-ynyl isocyanide, H3C-C triple bond C-N triple bond C, D3C-C triple bond C-N triple bond C: high resolution infrared specturm of prop-1-ynyl isocyanide

Ethynyl isocyanide, H-C triple bond C-N triple bond C (1a), deuteroethynyl isocyanide, D-C triple bond C-N triple bond C (1b), prop-1-ynyl isocyanide, H3C-C triple bond C-N triple bond C (1c), and trideuteroprop-1-ynyl isocyanide, D3C-C triple bond C-N triple bond C (1d) are synthesized by flash vacuum pyrolysis of suitable organometallic precursor molecules (CO)5Cr(CN-CCl triple bond CClH) (5a), (CO)5Cr(CN-CCI=CClD) (5b), (CO)5Cr(CN-CCl=CCl-CH3) (5c) and (CO)5Cr(CN-CCI=CCl-CD3) (5d), respectively. Compounds 5a-d are formed in two steps by radical alkylation of tetraethyl-ammonium pentacarbonyl(cyano)chromate, NEt4[Cr(CO)5(CN)] (2) by 1,1,2,2,-tetrachloroethane (3a), 1,1,2,2-tetrachloro-1,2-dideuteroethane (3b), 1,1,2,2,-tetrachloropropane (3c), and 1,1,2,2-tetrachloro- 1,3,3,3-tetradeutero-propane (3d) yielding [(CO)5Cr(CN-CCl2-CCl2-H)] (4a), [(CO)5Cr(CN-CCl2-CCl2D)] (4b), [(CO)5Cr(CN-CCl2-CCl2-CH3)] (4c), and [(CO)5Cr(CN-CCl2-CCl2-CD3)] (4d). Dehalogenation of 4a-d using zinc in diethylether/acetic acid gives 5a-d, respectively. A multinuclear NMR study revealed the 1H-, 13C- and 15N-NMR data of 1a and 1c. Molecular spectroscopic data of 1c were determined by high resolution infrared spectroscopy. The by-products of the pyrolysis are the E and Z isomers of the halogenated ethenyl isocyanides H(Cl)C=CCl-NC (6a) and H3C(Cl)C=CCl-NC (6c) which have been characterized by IR, MS and NMR spectroscopy.

Journal Article↗
PubMed2000

Oxidation-reduction properties of disulfide-containing proteins of the Rhodobacter capsulatus cytochrome c biogenesis system.

Oxidation-reduction titrations for the active-site disulfide/dithiol couples of the helX- and ccl2-encoded proteins involved in cytochrome c biogenesis in the purple non-sulfur bacterium Rhodobacter capsulatus have been carried out. The R. capsulatus HelX and Ccl2 proteins are predicted to function as part of a dithiol/disulfide cascade that reduces a disulfide on the apocytochromes c so that two cysteine thiols are available to form thioether linkages between the heme prosthetic group and the protein. Oxidation-reduction midpoint potential (E(m)) values, at pH 7.0, of -300 +/- 10 and -210 +/- 10 mV were measured for the HelX and Ccl2 (a soluble, truncated form of Ccl2) R. capsulatus proteins, respectively. Titrations of the disulfide/dithiol couple of a peptide designed to serve as a model for R. capsulatus apocytochrome c(2) have also been carried out, and an E(m) value of -170 +/- 10 mV was measured for the model peptide at pH 7.0. E(m) versus pH plots for HelX, Ccl2, and the apocytochrome c(2) model peptide were all linear over the pH range from 5.0 to 8.0, with the -59 mV/pH unit slope expected for a reaction in which two protons are taken up for each disulfide that is reduced. These results provide thermodynamic support for the proposal that HelX reduces Ccl2 and that reduced Ccl2, in turn, serves as the reductant for the production of the two thiols of the CysXxxYyyCysHis heme-binding motif of the apocytochromes.

Bacterial Proteins↗
PubMed2006

Chemokine (C-C motif) ligand 2 mediates the prometastatic effect of dysadherin in human breast cancer cells.

Dysadherin, a cancer-associated membrane glycoprotein, down-regulates E-cadherin and promotes cancer metastasis. This study examined the role of dysadherin in breast cancer progression. Expression of dysadherin was found to be highest in breast cancer cell lines and tumors that lacked the estrogen receptor (ER). Knockdown of dysadherin caused increased association of E-cadherin with the actin cytoskeleton in breast cancer cell lines that expressed E-cadherin. However, knockdown of dysadherin could still suppress cell invasiveness in cells that had no functional E-cadherin, suggesting the existence of a novel mechanism of action. Global gene expression analysis identified chemokine (C-C motif) ligand 2 (CCL2) as the transcript most affected by dysadherin knockdown in MDA-MB-231 cells, and dysadherin was shown to regulate CCL2 expression in part through activation of the nuclear factor-kappaB pathway. The ability of dysadherin to promote tumor cell invasion in vitro was dependent on the establishment of a CCL2 autocrine loop, and CCL2 secreted by dysadherin-positive tumor cells also promoted endothelial cell migration in a paracrine fashion. Finally, experimental suppression of CCL2 in MDA-MB-231 cells reduced their ability to metastasize in vivo. This study shows that dysadherin has prometastatic effects that are independent of E-cadherin expression and that CCL2 could play an important role in mediating the prometastatic effect of dysadherin in ER-negative breast cancer.

Actins↗
PubMed2005

Glycyrrhizin inhibits R5 HIV replication in peripheral blood monocytes treated with 1-methyladenosine.

R5 HIV replicated in freshly isolated human peripheral blood monocytes after treatment with 1-methyladenosine (fresh PBM/MA), an immunosuppressive compound isolated from tumorous ascites fluids, while viral replication was not demonstrated in untreated peripheral blood monocytes (fresh PBM). The R5 HIV replication in fresh PBM/MA was inhibited by glycyrrhizin (GL). Without any other stimulation, fresh PBM/MA produced CCL2 and IL-10, while these soluble factors were not released from fresh PBM. GL greatly inhibited the production of CCL2 and IL-10 in fresh PBM/MA. After treatment with CCL2 and/or IL-10, CCR5 mRNA expression in fresh PBM was markedly enhanced, while only a trace level of the mRNA expression was detected in these cells in the absence of CCL2 or IL-10. CCR5 mRNA expression in fresh PBM treated with CCL2 or IL-10 was clearly inhibited by GL. These results indicate that GL inhibits R5 HIV replication in fresh PBM/MA through the inhibiting CCR5 expression mediated by CCL2 or IL-10.

Adenosine↗
PubMed2004

Toxoplasma gondii triggers myeloid differentiation factor 88-dependent IL-12 and chemokine ligand 2 (monocyte chemoattractant protein 1) responses using distinct parasite molecules and host receptors.

Toll-like receptors (TLR) that signal through the common adaptor molecule myeloid differentiation factor 88 (MyD88) are essential in proinflammatory cytokine responses to many microbial pathogens. In this study we report that Toxoplasma gondii triggers neutrophil IL-12 and chemokine ligand 2 (CCL2; monocyte chemoattractant protein 1) production in strict dependence upon functional MyD88. Nevertheless, the responses are distinct. Although we identify TLR2 as the receptor triggering CCL2 production, parasite-induced IL-12 release did not involve this TLR. The production of both IL-12 and CCL2 was increased after neutrophil activation with IFN-gamma. However, the synergistic effect of IFN-gamma on IL-12, but not CCL2, was dependent upon Stat1 signal transduction. Although IL-10 was a potent down-regulator of Toxoplasma-triggered neutrophil IL-12 release, the cytokine had no effect on parasite-induced CCL2 production. Soluble tachyzoite Ag fractionation demonstrated that CCL2- and IL-12 inducing activities are biochemically distinct. Importantly, Toxoplasma cyclophilin-18, a molecule previously shown to induce dendritic cell IL-12, was not involved in neutrophil IL-12 production. Our results show for the first time that T. gondii possesses multiple molecules triggering distinct MyD88-dependent signaling cascades, that these pathways are independently regulated, and that they lead to distinct profiles of cytokine production.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Role of the CCL2/MCP-1 -2518A>G gene polymorphism in HLA-B27 associated uveitis.

PURPOSE: Acute anterior uveitis (AAU) is the most common form of uveitis. Up to 50% of patients with AAU are HLA-B27 positive. Since HLA B27 itself plays only a minor role in the overall genetic background, other genetic variants are likely to contribute to the susceptibility to AAU. The chemokine (C-C motif) ligand 2 (CCL2) gene, coding for monocyte chemoattractant protein-1 (MCP-1), a chemotactic cytokine, is involved in the induction of uveitis. A CCL2 gene polymorphism, which is characterized by an A>G substitution at nucleotide -2518 in the promoter region of CCL2 has been previously shown to affect MCP-1 synthesis. The purpose of the present study was to investigate a hypothesized association between this genetic variant and the presence of HLA-B27 associated AAU. METHODS: The study group comprised 114 patients with HLA-B27 associated AAU. One hundred and eleven healthy HLA-B27 positive individuals served as the HLA-B27 positive control group, whereas 81 healthy HLA-B27 negative individuals served as a HLA-B27 negative control group. Genotyping for the CCL2 -2518A>G polymorphism was performed by polymerase chain reaction. RESULTS: Carriers of a CCL2 -2518G allele were found significantly more often in patients with HLA-B27 associated AAU than among HLA-B27 positive controls (49.2% and 31.5%, respectively; odds ratio 2.1; 95% confidence interval 1.2-3.6; p=0.007). CONCLUSIONS: Our data suggest that the CCL2 -2518A>G polymorphism may play a role in HLA-B27 associated acute anterior uveitis.

Acute Disease↗
PubMed2005

The singlet-triplet separation in CF2: state-of-the-art ab initio calculations and Franck-Condon simulations including anharmonicity.

Geometrical parameters, vibrational frequencies and relative electronic energies of the X2B1 state of CF2- and the X1A1 and ã3B1 states of CF2 have been calculated. Core-electron effects on the computed minimum-energy geometries and relative electronic energies have been investigated, and relativistic contributions to the computed relative electronic energies calculated. Potential energy functions of the X2B1 state of CF2- and the X1A1 and ã3B1 states of CF2 have been determined, and anharmonic vibrational wavefunctions of these states calculated variationally. Franck-Condon factors including anharmonicity and Duschinsky rotation have been computed and used to simulate the ã-X emission spectrum of CF2 determined by S. Koda [Chem. Phys. Lett. 1978, 55, 353] and the 364 nm laser photodetachment spectrum of CF2- obtained by R. L. Schwartz et al. [J. Phys. Chem. A 1999, 103, 8213]. Comparison between theory and experiment shows that the theoretical approach benchmarked in the present study is able to give highly reliable positions for the CF2(X1A1) + e <-- CF2-(X2B1) and CF2(ã3B1) + e <-- CF2-(X2B1) bands in the photoelectron spectrum of CF2- and a reliable singlet-triplet gap for CF2. It is therefore concluded that the same theoretical approach should give reliable simulated CCl2(X1A1) + e <-- CCl2-(X2B1) and CCl2(ã3B1) + e <-- CCl2-(X2B1) bands in the photodetachment spectrum of CCl2- and a reliable singlet-triplet gap for CCl2.

Journal Article↗
PubMed2002

Distinct roles of receptor phosphorylation, G protein usage, and mitogen-activated protein kinase activation on platelet activating factor-induced leukotriene C(4) generation and chemokine production.

Platelet activating factor (PAF) interacts with cell surface G protein-coupled receptors on leukocytes to induce degranulation, leukotriene C(4) (LTC(4)) generation, and chemokine CCL2 production. Using a basophilic leukemia RBL-2H3 cell line expressing wild-type PAF receptor (PAFR) and a phosphorylation-deficient mutant (mPAFR), we have previously demonstrated that receptor phosphorylation mediates desensitization of PAF-induced degranulation. Here, we sought to determine the role of receptor phosphorylation on PAF-induced LTC(4) generation and CCL2 production. We found that PAF caused a significantly enhanced LTC(4) generation in cells expressing mPAFR when compared with PAFR cells. In contrast, PAF-induced CCL2 production was greatly reduced in mPAFR cells. Pertussis toxin and U0126, which inhibit G(i) and p44/42 mitogen-activated protein kinase (ERK) activation, respectively, caused very little inhibition of PAF-induced CCL2 production (approximately 20% inhibition). In contrast, these inhibitors almost completely blocked both PAF-induced ERK phosphorylation and LTC(4) generation in PAFR cells. However, in mPAFR cells pertussis toxin only partially inhibited PAF-induced ERK phosphorylation. A Ca(2+)/calmodulin inhibitor had no effect on PAF-induced ERK phosphorylation in PAFR cells but completely blocked the response in mPAFR cells. These data demonstrate that receptor phosphorylation, which serves to desensitize PAF-induced LTC(4) generation, is required for chemokine CCL2 production. They also indicate a previously unrecognized selectivity in G protein usage and ERK activation for PAF-induced responses. Whereas PAF-induced CCL2 production is, in large part, mediated independently of G(i) activation or ERK phosphorylation, LTC(4) generation requires ERK phosphorylation, which is mediated by different G proteins depending on the phosphorylation status of the receptor.

Calcium↗
PubMed2006

Monocyte chemoattractant protein-1-induced tissue inflammation is critical for the development of renal injury but not type 2 diabetes in obese db/db mice.

AIMS/HYPOTHESIS: Tissue macrophage accumulation is thought to induce insulin resistance during obesity and stimulate the progression of diabetic nephropathy. Monocyte chemoattractant protein-1 (MCP-1) is a potent stimulator of macrophage recruitment. It is increased in adipose tissue during obesity and in diabetic kidneys, suggesting that inflammation of these tissues may be MCP-1-dependent. Based on these findings, the aim of this study was to examine whether a deficiency in MCP-1 would alter the development of type 2 diabetes and its renal complications. MATERIALS AND METHODS: The role of MCP-1 in the progression of type 2 diabetes and its associated renal injury was assessed in obese db/db mice that were deficient in the gene encoding MCP-1 (Ccl2). RESULTS: The incidence and development of type 2 diabetes were similar in Ccl2(+/+) and Ccl2(-/-) db/db mice between 8 and 32 weeks of age. Body mass, hyperglycaemia, hyperinsulinaemia, glucose and insulin tolerance, plasma triacylglycerol and serum NEFA were not different between these strains. Pathological changes in epididymal adipose tissue, including increases in macrophage accumulation and Tnfa mRNA and reductions in Adipoq mRNA, were unaffected by the absence of MCP-1. In contrast, kidney macrophage accumulation and the progression of diabetic renal injury (albuminuria, histopathology, renal fibrosis) were substantially reduced in Ccl2(-/-) compared with Ccl2(+/+) db/db mice with equivalent diabetes. CONCLUSIONS/INTERPRETATION: Our study demonstrates that MCP-1 promotes type 2 diabetic renal injury but does not influence the development of obesity, insulin resistance or type 2 diabetes in db/db mice. MCP-1 plays a critical role in inflammation of the kidney, but not adipose tissue, during the progression of type 2 diabetes.

Animals↗
PubMed2005

Perturbation of chemokine networks by gene deletion alters the reinforcing actions of ethanol.

Microarray analysis of human alcoholic brain and cultured cells exposed to ethanol showed significant changes in expression of genes related to immune or inflammatory responses, including chemokines and chemokine receptors. To test the hypothesis that chemokines exhibit previously undiscovered pleiotropic effects important for the behavioral actions of ethanol, we studied mutant mice with deletion of the Ccr2, Ccr5, Ccl2 or Ccl3 genes. Deletion of Ccr2, Ccl2 (females) or Ccl3 in mice resulted in lower preference for alcohol and consumption of lower amounts of alcohol in a two-bottle choice test as compared with wild-type mice. Ethanol treatment (2.5 g/kg, i.p.) induced stronger conditioned taste aversion in Ccr2, Ccl2 or Ccl3 null mutant mice than in controls. Ccr2 and Ccr5 null mutant mice did not differ from wild-type mice in ethanol-induced loss of righting reflex (LORR), but mice lacking Ccl2 or Ccl3 showed longer LORR than wild-type mice. There were no differences between mutant strains and wild-type mice in severity of ethanol-induced withdrawal. Genetic mapping of chromosome 11 for the Ccl2 and Ccl3 genes (46.5 and 47.6 cM, respectively) revealed that an alcohol-induced LORR QTL region was contained within the introgressed region derived from 129/SvJ, which may cause some behavioral phenotypes observed in the null mice. On the contrary, known QTLs on Chr 9 are outside of 129/SvJ region in Ccr2 and Ccr5 (71.9 and 72.0 cM, respectively) null mutant mice. These data show that disruption of the chemokine network interferes with motivational effects of alcohol.

Alcohol Drinking↗
PubMed2006

Caveolin-1 regulates expression of junction-associated proteins in brain microvascular endothelial cells.

Recent evidence from this laboratory indicated that reduced expression of caveolin-1 accompanied the diminished expression of tight junction (TJ)-associated proteins occludin and zonula occludens-1 (ZO-1) following stimulation of brain microvascular endothelial cells (BMECs) with the chemokine CCL2 (formerly called MCP-1). Because attenuated caveolin-1 levels have also been correlated with heightened permeability of other endothelia, the objective of this study was to test the hypothesis that reduced caveolin-1 expression is causally linked to the action of CCL2 on BMEC junctional protein expression and barrier integrity. This was achieved using adenovirus to nondestructively deliver caveolin-1 siRNA (Ad-siCav-1) to BMEC monolayers, which model the blood-brain barrier (BBB). Treatment with siRNA reduced the caveolin-1 protein level as well as occludin and ZO-1. Additionally, occludin exhibited dissociation from the cytoskeletal framework. These changes were attended by comparable alterations in adherens junction (AJ)-associated proteins, VE-cadherin and beta-catenin, increased BMEC paracellular permeability, and facilitated the ability of CCL2 to stimulate monocytic transendothelial migration. Furthermore, treating BMECs with cavtratin, a synthetic cell-permeable peptide encoding the caveolin-1 scaffolding domain, antagonized effects of both Ad-siCav-1 and CCL2. These results collectively highlight caveolin-1 loss as a critical step in CCL2-induced modulation of BMEC junctional protein expression and integrity, and possibly serve a crucial role in regulating inflammation at the BBB.

Animals↗
PubMed2004

Regulation of monocyte chemokine and MMP-9 secretion by proinflammatory cytokines in tuberculous osteomyelitis.

Tuberculous osteomyelitis causes bony destruction as a result of interactions among the pathogen, resident bone cells, and influxing leukocytes. Recruitment of monocytes and T cells is critical for antimycobacterial granuloma formation, but little is known about mechanisms regulating this in bone. We investigated the role of tumor necrosis factor alpha (TNF-alpha) and interleukin (IL)-1, key cytokines in granuloma formation, in networks involving human osteoblasts and monocytes. Experiments focused on CXC ligand (CXCL)8, CCL2, and matrix metalloproteinase (MMP)-9, human monocyte-derived mediators involved in control of leukocyte influx. TNF-alpha but not IL-1 has a key role stimulating CXCL8 secretion in Mycobacterium tuberculosis-infected human osteoblast MG-63 cells. Conditioned medium from M. tuberculosis-infected osteoblasts (COBTB) drives CXCL8 and some CCL2 gene expression and secretion from primary human monocytes. IL-1 receptor antagonist and to a lesser extent anti-TNF-alpha inhibited COBTB-induced CXCL8 secretion (P<0.01) but did not affect gene expression. IL-1 blockade had a comparatively lesser effect on CCL2 secretion, whereas anti-TNF decreased CCL2 concentrations from 7840 +/- 140 to 360 +/- 80 pg/ml/4 x 10(5) cells. Neither proinflammatory mediator affects MMP-9 secretion from COBTB-stimulated human monocytes. In summary, in a paracrine network, M. tuberculosis-infected osteoblasts drive high-level CXCL8, comparatively less CCL2, but do not alter MMP-9 secretion from uninfected human monocytes. This network is, in part, regulated by IL-1 and TNF-alpha.

Cells, Cultured↗
PubMed2006

Assessment of genetic effects of polymorphisms in the MCP-1 gene on serum MCP-1 levels and myocardial infarction in Japanese.

BACKGROUND: Recently, the Framingham Heart Study reported that genetic variations in CCL2 influence serum levels of monocyte chemoattractant protein-1 (MCP-1) and the incidence of myocardial infarction (MI). The purpose of the present study was to investigate the possible involvement of CCL2 in the pathogenesis of atherosclerosis and MI in Japanese. METHODS AND RESULTS: Multiple regression analysis indicated that the MCP-1 levels were significantly influenced by various factors including age, body mass index, smoking, alcohol intake, high density lipoprotein-cholesterol, and systolic blood pressure. Moreover, the serum MCP-1 level was significantly correlated with intima - media thickness (p < 0.0001). However, this association disappeared when other clinical confounding factors were included in the analyses. Comprehensive analysis of common polymorphisms of CCL2 in a large community-based population and in subjects with MI found that the A(-2138)T polymorphism affected the serum MCP-1 level in a subgroup of subjects 65 years and older. However, no significant differences in the frequencies of any of the polymorphisms or haplotypes were found between subjects with and without MI. None of the polymorphisms in CCL2 affected carotid atherosclerosis. CONCLUSIONS: The serum MCP-1 level was a good surrogate marker of atherosclerosis in the present study population. Although genetic variations in CCL2 may have some influence on MCP-1 production, their influence does not seem to contribute appreciably to atherosclerosis in Japanese. The present results did not support the recently published findings from the Framingham Heart Study. The discrepancy between the 2 studies may be related to differences in confounding factors that contribute to MCP-1 levels and in the haplotype structure of the 2 populations.

Aged↗
PubMed2006

CCL2/monocyte chemoattractant protein-1 mediates enhanced transmigration of human immunodeficiency virus (HIV)-infected leukocytes across the blood-brain barrier: a potential mechanism of HIV-CNS invasion and NeuroAIDS.

Encephalitis and dementia associated with acquired immunodeficiency syndrome (AIDS) are characterized by leukocyte infiltration into the CNS, microglia activation, aberrant chemokine expression, blood-brain barrier (BBB) disruption, and eventual loss of neurons. Little is known about whether human immunodeficiency virus 1 (HIV-1) infection of leukocytes affects their ability to transmigrate in response to chemokines and to alter BBB integrity. We now demonstrate that HIV infection of human leukocytes results in their increased transmigration across our tissue culture model of the human BBB in response to the chemokine CCL2, as well as in disruption of the BBB, as evidenced by enhanced permeability, reduction of tight junction proteins, and expression of matrix metalloproteinases (MMP)-2 and MMP-9. HIV-infected cells added to our model did not transmigrate in the absence of CCL2, nor did this condition alter BBB integrity. The chemokines CXCL10/interferon-gamma-inducible protein of 10 kDa, CCL3/macrophage inflammatory protein-1alpha, or CCL5/RANTES (regulated on activation normal T-cell expressed and secreted) did not enhance HIV-infected leukocyte transmigration or BBB permeability. The increased capacity of HIV-infected leukocytes to transmigrate in response to CCL2 correlated with their increased expression of CCR2, the chemokine receptor for CCL2. These data suggest that CCL2, but not other chemokines, plays a key role in infiltration of HIV-infected leukocytes into the CNS and the subsequent pathology characteristic of NeuroAIDS.

AIDS Dementia Complex↗
PubMed2006

Dynamics of the 193 nm photodissociation of dichlorocarbene.

The dynamics of the 193 nm photodissociation of the CCl2 molecule have been investigated in a molecular beam experiment. The CCl2 parent molecule was generated in a molecular beam by pyrolysis of CHCl3, and both CCl2 and the CCl photofragment were detected by laser fluorescence excitation. The 193 nm attenuation cross section was estimated from the reduction of the CCl2 signal as a function of the photolysis laser fluence. The internal state distribution of the CCl photofragment was derived from analysis of laser fluorescence excitation spectra in the A 2Delta-X 2Pi band system. Most of the energy available to the CCl(X 2Pi)+Cl fragments appears as translational energy. The CCl fragment rotational energy is much less than predicted in an impulsive model. The excited electronic state appears to dissociate indirectly, through coupling with a repulsive state arising from the ground-state CCl(X 2Pi)+Cl asymptote. The identity of the initially excited electronic state is discussed on the basis of what is known about the CCl2 electronic states.

Journal Article↗
PubMed2002

Expression of chemokines in the CSF and correlation with clinical disease activity in patients with multiple sclerosis.

OBJECTIVE: To define the chemokine profile in the CSF of patients with multiple sclerosis (MS) and compare it with three control groups; patients with benign headache (headache), non-inflammatory neurological diseases (NIND), and other inflammatory neurological diseases (IND). In addition, the correlations of CSF chemokine concentrations with chemokine receptor expression on CSF CD4(+) T cells and with clinical disease activity were assessed. METHODS: Forty three patients with MS, 24 with IND, 44 with NIND, and 12 with benign headache undergoing diagnostic or therapeutic lumbar puncture were included. Supernatant fluid from CSF was analysed for four beta (CCL2, CCL3, CCL4, CCL5) and two alpha (CXCL9, CXCL10)chemokines by enzyme linked immunosorbent assay (ELISA). Chemokine receptors CCR3, CCR5, and CXCR3 on CD4(+) T cells from eight patients with MS were analysed using directly conjugated fluorescent labelled monoclonal antibodies and flow cytometry. RESULTS: CXCL10, formerly interferon-gamma inducible protein-10 (IP-10), was significantly increased and CCL2, formerly monocyte chemoattractant protein-1 (MCP-1), was significantly reduced in the CSF of patients with MS and IND compared with those with benign headache and NIND. Concentrations of CXCL10 were significantly greater in patients with relapsing-remitting compared with secondary progressive MS and correlated significantly with CXCR3 expression on CSF CD4(+) T cells from patients with MS. Concentrations of CXCL10 decreased and CCL2 concentrations increased as time from the last relapse increased in patients with MS. CONCLUSION: Increased CXCL10 and decreased CCL2 concentrations in the CSF are associated with relapses in MS. Although serial values from individual patients were not available, this study suggests that CXCL10 and CCL2 may return towards baseline concentrations after a relapse. Correlation of CXCL10 with CD4(+) T cell expression of CXCR3 was consistent with its chemoattractant role for activated lymphocytes. Thus CXCL10 neutralising agents and CXCR3 receptor antagonists may be therapeutic targets in MS.

Adult↗
PubMed2006

Bacterial sepsis and chemokines.

Bacterial sepsis causes a high mortality rate when it occurs in patients with compromised host defenses. Severely burned patients, typical immunocompromised hosts, are extremely susceptible to infections from various pathogens, and a local wound infection frequently escalates into sepsis. In these patients, Staphylococcus aureus, Enterococcus faecalis and Pseudomonas aeruginosa are familiar pathogens that cause opportunistic infections. Also, polymicrobial sepsis frequently occurs in these patients. In this review, therefore, the roles of chemokines in thermally injured patients infected with these 3 pathogens and polymicrobial sepsis will be discussed. These infections in thermally injured patients may be controlled immunologically, because immunocompetent hosts are resistant to infections with these pathogens. Classically activated macrophages (M1Mphi) are major effector cells for host innate immune responses against these infections. However, M1Mphi are not generated in thermally injured patients whose alternatively activated macrophages (M2Mphi) predominate. M2Mphi appear in patients early after severe burn injuries. M2Mphi inhibit M1Mphi generation through the secretion of CCL17 and IL-10. As a modulator of Mphi, two different subsets of neutrophils (PMN-I, PMN-II) are described. PMN-I direct the polarization of resident Mphi into M1Mphi through the production of CCL3. M2Mphi are induced from resident Mphi by CCL2 released from PMN-II. Therefore, as an inhibitor of CCL2, glycyrrhizin protects individuals infected with S. aureus. Sepsis stemming from P. aeruginosa wound infection is also influenced by CCL2 released from immature myeloid cells. A large number of immature myeloid cells appear in association with burn injuries. Host resistance to S. aureus, E. faecalis, P. aeruginosa or polymicrobial infections may be improved in thermally injured patients through the induction of M1Mphi, elimination of CCL2 and/or depletion of M2Mphi induced by CCL2.

Animals↗
PubMed2006

Glycyrrhizin inhibits the manifestations of anti-inflammatory responses that appear in association with systemic inflammatory response syndrome (SIRS)-like reactions.

In association with the systemic inflammatory response syndrome (SIRS), anti-inflammatory response syndrome is commonly manifested in patients with trauma, burn injury, and after major surgery. These patients are increasingly susceptible to infection with various pathogens due to the excessive release of anti-inflammatory cytokines from anti-inflammatory effector cells. Recently, CC-chemokine ligand 2 (CCL2) found in the sera of mice with pancreatitis was identified as an active molecule for SIRS-associated anti-inflammatory response manifestation. Also, the inhibitory activity of glycyrrhizin (GL) on CCL2 production was reported. Therefore, the effect of GL on SIRS-associated anti-inflammatory response manifestation was investigated in a murine SIRS model. Without any stimulation, splenic T cells from mice 5 days after SIRS induction produced cytokines associated with anti-inflammatory response manifestation. However, these cytokines were not produced by splenic T cells from SIRS mice previously treated with GL. In dual-chamber transwells, IL-4-producing cells were generated from normal T cells cultured with peripheral blood polymorphonuclear neutrophils (PMN) from SIRS mice. However, IL-4-producing cells were not generated from normal T cells in transwell cultures performed with PMN from GL-treated SIRS mice. CCL2 was produced by PMN from SIRS mice, while this chemokine was not demonstrated in cultures of PMN from SIRS mice treated with GL. These results indicate that GL has the capacity to suppress SIRS-associated anti-inflammatory response manifestation through the inhibition of CCL2 production by PMN.

Animals↗