Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P80098 (monocyte chemoattractant protein)
 1,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chemokines may regulate the process of immune cell infiltration that is often found in pancreatic cancer. In this study, we investigated the secretion of the chemokines [interleukin (IL)-8, monocyte chemoattractant protein (MCP)-1, and RANTES (regulated on activation, normal T cell expressed and secreted)] in human pancreatic cancer cell lines. The chemokine secretion in three pancreatic cancer cell lines (PANC-1, MIA PaCa-2, and BxPC-3) was evaluated by enzyme-linked immunosorbent assay (ELISA) and Northern blot, and the activation of nuclear factor-kappaB (NF-kappaB) and NF-IL6 was assessed by an electrophoretic gel mobility shift assay (EMSA). Without any stimulation, IL-8 secretion was detected in all cell lines, and MCP-1 secretion was detected in PANC-1 and MIA PaCa-2 cells. However, RANTES secretion was not detected in all cells. The addition of IL-1beta and tumor necrosis factor (TNF)-alpha strongly enhanced IL-8, MCP-1, and RANTES secretion; these responses were observed at the mRNA level as well as at the protein level. IL-1beta and TNF-alpha induced a rapid activation of nuclear factor (NF)-kappaB in PANC-1 cells, and the increase in chemokine mRNA expression correlated with NF-kappaB activation. The activation of NF-IL6 was modest. A blockade of NF-kappaB activation by TPCK markedly reduced the IL-1beta- and TNF-alpha-induced chemokine gene expression. Our findings indicate that chemokines are produced by pancreatic cancer cells, and suggest that these factors may contribute to the accumulation of tumor-associated immune cells. In addition, the transcriptional activation of chemokine genes in pancreatic cancer cells may be closely associated with NF-kappaB activation.
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PMID:The expression of chemokine genes correlates with nuclear factor-kappaB activation in human pancreatic cancer cell lines. 1088 30

Chemokines are involved in recruitment and activation of hematopoietic cells at sites of infection and inflammation. The M3 gene of gammaHV68, a gamma-2 herpesvirus that infects and establishes a lifelong latent infection and chronic vasculitis in mice, encodes an abundant secreted protein during productive infection. The M3 gene is located in a region of the genome that is transcribed during latency. We report here that the M3 protein is a high-affinity broad-spectrum chemokine scavenger. The M3 protein bound the CC chemokines human regulated upon activation of normal T-cell expressed and secreted (RANTES), murine macrophage inflammatory protein 1alpha (MIP-1alpha), and murine monocyte chemoattractant protein 1 (MCP-1), as well as the human CXC chemokine interleukin-8, the murine C chemokine lymphotactin, and the murine CX(3)C chemokine fractalkine with high affinity (K(d) = 1. 6 to 18.7 nM). M3 protein chemokine binding was selective, since the protein did not bind seven other CXC chemokines (K(d) > 1 microM). Furthermore, the M3 protein abolished calcium signaling in response to murine MIP-1alpha and murine MCP-1 and not to murine KC or human stromal cell-derived factor 1 (SDF-1), consistent with the binding data. The M3 protein was also capable of blocking the function of human CC and CXC chemokines, indicating the potential for therapeutic applications. Since the M3 protein lacks homology to known chemokines, chemokine receptors, or chemokine binding proteins, these studies suggest a novel herpesvirus mechanism of immune evasion.
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PMID:Identification of a gammaherpesvirus selective chemokine binding protein that inhibits chemokine action. 1088 12

Infiltration of hematogenous lineage cells into the central nervous system (CNS) was investigated in the twitcher mouse, a murine model of globoid cell leukodystrophy in human. The hematogenous cells were selectively labeled following intraperitoneal injection of rhodamine isothiocyanate (RhIc). The frequency of detecting Rhlc-labeled cells (Rhlc+ cells) in the twitcher CNS varied with age. RhIc+ cells were hardly detected when injection was made prior to the postnatal day (PND) 30. The number of Rhlc' cells increased thereafter peaked at PND 35-38 and declined drastically at PND 40-45. The majority of RhIc+ cells were distributed in white matter of the CNS that correlated well with the areas of demyelination and of increased microglia/macrophage population described in our earlier studies. Almost all Rhlc+ cells were double-labeled with antibody for Mac-1 and also with MHC class II. Some small cells double-labeled with RhIc and antibodies for CD4, CD8, or IL-2R were also identified. By RT-PCR, the expression of monocyte chemoattractant protein- (MCP-1) mRNA increased drastically at PND 30, peaked at PND 35, and decreased gradually after PND 40. This pattern of mRNA changes correlated well with the dynamic pattern of the infiltration of hematogenous cells into the CNS, suggesting a role of chemokine(s) in the cellular infiltration in the twitcher brain. The expression of IL-10 mRNA also increased gradually. IL-10 is a cytokine inhibitory factor and a major regulator in suppressing the inflammatory response. Thus, our results indicated that hematogenous lineage cells infiltrated in the CNS of twitcher mice, and that MCP-1 and IL-10 may play an important role in regulating the cellular recruitment.
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PMID:Infiltration of hematogenous lineage cells into the demyelinating central nervous system of twitcher mice. 1090 Dec 35

The chemokine fractalkine (FK) has two structural features that make it unique in the chemokine family: a CX(3)C motif and an extended carboxyl terminus that anchors it to the cell surface. This mucin-like stalk or an equivalent spacer is required for FK to mediate the adhesion of cells expressing its receptor, CX(3)CR1. To determine whether the ability of FK to act as a cell adhesion molecule is due to the unique presentation of a chemokine domain on a stalk or to properties of the chemokine domain itself, we created a series of chimeras in which other soluble chemokines (RANTES (regulated on activation normal T cell expressed), monocyte chemoattractant protein 1, macrophage inflammatory protein 1 beta, secondary lymphoid tissue chemokine, and interleukin 8) were fused to the mucin stalk. When tested in a static-cell adhesion assay, many of these chemokine chimeras demonstrated activity equivalent to that of FK. In flow assays, however, none of the chimeras captured cells as efficiently as FK. Interestingly, FK captured cells expressing either CX(3)CR1 or the viral receptor US28. Cells bound to FK without rolling or detaching, whereas the interleukin 8 and monocyte chemoattractant protein 1 chimeras induced primarily cell rolling and detaching, respectively. In binding studies, FK has a significantly slower off-rate from its receptors than any of the other chemokine chimeras had for their cognate receptors. We conclude that presentation of a chemokine atop a mucin-like stalk is not, in and of itself, sufficient to capture cells. The unique ability of FK to mediate adhesion under flow may be a function of its slow receptor off-rate.
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PMID:Unique role of the chemokine domain of fractalkine in cell capture. Kinetics of receptor dissociation correlate with cell adhesion. 1094 Mar 7

Thalidomide, a psychoactive drug that readily crosses the blood-brain barrier, has been shown to possess immunomodulatory attributes, including the inhibition of cytokine production by monocytes and microglia. In this study, we investigated the effect of thalidomide on chemokine production by human microglial cells. Microglial cells were stimulated with lipopolysaccharide, a key cell-wall component of gram-negative bacteria responsible for meningitis, and production of chemokines (regulated upon activation normally T cell expressed and secreted [RANTES], monocyte chemoattractant protein [MCP]-1, macrophage inflammatory protein [MIP]-1beta, and interleukin [IL]-8) was examined by ELISA. Thalidomide treatment was found to cause potent and selective inhibition of IL-8 production in a dose-responsive manner. This inhibition was associated with decreased intracellular IL-8 staining as well as reduced transcription of IL-8 mRNA. In addition, thalidomide treatment of lipopolysaccharide-stimulated microglia inhibited the activation of protein NF-kappaB, a transcription factor known to be important for IL-8 production. These results suggest thalidomide could have a therapeutic role in acute bacterial meningitis through inhibition of IL-8-mediated neutrophil chemotaxis.
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PMID:Effect of thalidomide on chemokine production by human microglia. 1095 Aug 3

Infection by human T-cell leukemia virus type (HTLV) I leads to adult T-cell leukemia and is also associated with the neurodegenerative disease HTLV-I-associated myelopathy/tropical spastic paraparesis. Leukocytes are attracted to sites of inflammation by chemokines. One such chemokine is monocyte chemoattractant protein (MCP)-1, a member of the C-C subfamily of chemokines. We investigated whether HTLV-I infection causes up-regulation of MCP-1, which may in turn cause recruitment of leukocytes to HTLV-I-infected areas. We now report that MCP-1 mRNA levels are elevated in HTLV-I-infected T-cell lines, when compared with uninfected ones. We further confirmed secretion of MCP-1 by HTLV-I-infected T-cell lines. MCP-1 mRNA was also expressed in leukemic cells from patients with adult T-cell leukemia. The 5' transcriptional regulatory region of the MCP-1 gene was activated by the HTLV-I-encoded transactivator Tax in the human T-cell line Jurkat, in which endogenous MCP-1 is induced by Tax. By using site-specific point mutations, we have identified two closely spaced nuclear factor (NF)-kappaB sites, A1 and A2, to be important for Tax-mediated transactivation of the MCP-1 gene. Through the use of an electrophoretic mobility shift assay, we demonstrated that Tax induced NF-kappaB binding to both MCP-1 kappaB sites. This is the first report to demonstrate that Tax can transactivate the MCP-1 gene through the induction of NF-kappaB. Our results thus reveal how Tax disrupts the normally regulated MCP-1 gene and leads to its constitutive expression in HTLV-I-infected cells. These findings may have important implications for our understanding of HTLV-I-associated diseases.
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PMID:Human T-cell leukemia virus type I tax activates transcription of the human monocyte chemoattractant protein-1 gene through two nuclear factor-kappaB sites. 1098 10

The cDNA expression array technique is a powerful tool to determine, at one time from many genes, specific gene messages modulated by infection. In the present study, we identified genes modulated in response to virulent versus avirulent Legionella pneumophila infection of the alveolar macrophage cell line MH-S by the cDNA expression array technique. Many macrophage genes were found to be modulated after 5 h of in vitro infection with L. pneumophila. In particular, it was found that the monocyte chemotactic protein 3 (MCP-3) gene expression was significantly induced by infection with virulent L. pneumophila but not with avirulent L. pneumophila. In contrast, other chemokine genes, such as macrophage inflammatory protein (MIP) 1alpha, were induced by both virulent and avirulent L. pneumophila. Reverse transcription (RT)-PCR assay of total RNA isolated from macrophages infected with the bacteria for 5 or 24 h confirmed the differential induction of the chemokine genes by virulent versus avirulent L. pneumophila. Thus, the cDNA expression array technique readily revealed differential induction by L. pneumophila infection of select chemokine genes of macrophages from more than 1,100 genes. These results also indicate that certain chemokine genes may be selectively induced by virulent bacteria.
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PMID:Differential effects of virulent versus avirulent Legionella pneumophila on chemokine gene expression in murine alveolar macrophages determined by cDNA expression array technique. 1099 25

Chemokines are a family of structurally related cytokines that activate and recruit leukocytes into areas of inflammation. The "CC" chemokine, monocyte chemoattractant protein (MCP)-1 may regulate the microglia/monocyte response to acute brain injury. Recent studies have documented increased expression of MCP-1 in diverse acute and chronic experimental brain injury models; in contrast, there is little information regarding expression of the MCP-1 receptor, CCR2, in the brain. In the neonatal rat brain, acute excitotoxic injury elicits a rapid and intense microglial response. To determine if MCP-1 could be a regulator of this response, we evaluated the impact of excitotoxic injury on MCP-1 and CCR2 expression in the neonatal rat brain. We used a reproducible model of focal excitotoxic brain injury elicited by intrahippocampal injection of NMDA (10 nmol) in 7-day-old rats, to examine injury-induced alterations in MCP-1 and CCR2 expression. RT-PCR assays demonstrated rapid stimulation of both MCP-1 and CCR2 mRNA expression. MCP-1 protein content, measured by ELISA in tissue extracts, increased >30-fold in lesioned tissue 8-12 h after lesioning. CCR2 protein was also detectable in tissue extracts. Double-immunofluorescent labeling enabled localization of CCR2 both to activated microglia/monocytes in the corpus callosum adjacent to the lesioned hippocampus and subsequently in microglia/monocytes infiltrating the pyramidal cell layer of the lesioned hippocampus. These results demonstrate that in the neonatal brain, acute excitotoxic injury stimulates expression of both MCP-1 and its receptor, CCR2, and suggests that MCP-1 regulates the microglial/monocyte response to acute brain injury.
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PMID:Acute excitotoxic injury induces expression of monocyte chemoattractant protein-1 and its receptor, CCR2, in neonatal rat brain. 1099 90

Recruitment of inflammatory cells is of critical importance in the pathogenesis of immune-mediated demyelinating diseases in the peripheral nervous system (PNS). Evidence is increasing that chemokines might play a key role in this process, since they promote leukocyte entry into the nervous system during immune-mediated inflammation. In the present study we report the expression pattern of the chemokines interferon-gamma-inducible protein (IP)-10, monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, and regulated upon activation normal T cell expressed and secreted (RANTES) in sciatic nerves from animals with myelin-induced experimental autoimmune neuritis, using a semiquantitative reverse transcriptase-PCR dot-blot hybridization assay. The mRNAs for MIP-1alpha and MIP-1beta were found to be upregulated with peak values at day 13 post-immunization (p.i.), preceding maximum disease severity. In contrast, mRNAs for MCP-1, RANTES, and IP-10 exhibited peak levels coincident with peak of the disease at day 15 p.i. Increased mRNA expression was associated with enhanced protein levels, as demonstrated by immunoblotting for each chemokine investigated. Immunohistochemistry for IP-10 protein revealed immunoreactivity associated with perineurial endothelial cells. RANTES protein was localized immunohistologically to invading T lymphocytes. Our findings suggest that chemokines, which act towards T cells and mononuclear phagocytes, are sequentially upregulated during the clinical course of EAN and thus may contribute to the pathogenesis of inflammatory demyelinating diseases of the PNS.
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PMID:Sequential expression of chemokines in experimental autoimmune neuritis. 1102 41

Among the inflammatory cells infiltrating the lungs of asthmatic patients, eosinophils and Th2 cells are thought to play a central role in the pathogenesis of this disease. Several studies have implicated that chemokines are prime candidates for being responsible for the selective recruitment of the leukocyte subsets found in atopic diseases. Regulated upon activation, normal T-cell-expressed and secreted (RANTES), monocyte chemoattractant protein-3 (MCP-3), MCP-4 and the eotaxins, for example, have been shown in vitro to potently induce eosinophil chemotaxis as well as initiate several other pro-inflammatory activities such as integrin activation, lipid mediator biosynthesis and degranulation. Ligand binding and chemotaxis experiments with these chemokines demonstrated that a G-protein coupled-receptor (GPCR) cloned from eosinophils, termed CCR3, was responsible for producing a chemokine selectivity profile identical to that of eosinophils. In addition, blocking CCR3 on eosinophils, with a monoclonal antibody, completely abolished eosinophil responses to these chemokines. Together these studies strongly suggest a central role for this receptor in eosinophil trafficking. CCR3 has also been found on in vitro derived Th2 cells and on T-cells co-localising with eosinophils in diseased tissue, thus revealing a possible pathogenic mechanism for T-cell recruitment into the airways. Therefore, blockade of CCR3 represents a highly attractive and innovative strategy for asthma therapy.
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PMID:CCR3 blockade as a new therapy for asthma. 1106 Jun 59


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