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)

Considerable evidence suggests that monocytes/macrophages play a crucial role in the process of liver injury and repair. Recent investigations have focused on the function of various macrophage-produced cytokines in liver disease. Much is still unknown, however, about the mechanism of macrophage recruitment and activation during liver disease. To further define this process, the gene expression of the monocyte chemoattractant monocyte chemoattractant protein 1 (MCP-1) was examined in animal and human liver disease. MCP-1 mRNA was not found in normal rat liver by Northern blot analysis. After single-dose treatments with the hepatotoxins carbon tetrachloride and galactosamine, MCP-1 mRNA was detectable beginning at 2 and 4 h after treatment, respectively, and was expressed continuously until 60-72 h. During chronic carbon tetrachloride administration, MCP-1 mRNA levels were elevated for the entire 10 weeks of treatment with peak levels of expression occurring early (weeks 1-3) and late (weeks 8-10) in this model. Isolated liver cell fractions from rats treated for 3 weeks with carbon tetrachloride revealed the major cellular source of MCP-1 mRNA to be fat-storing or Ito cells, with some expression occurring in the endothelial cell fraction. Studies of potential inducers of hepatic MCP-1 expression showed that lipopolysaccharide, tumor necrosis factor-alpha, and interleukin-1 alpha and beta treatments all led to MCP-1 expression. Finally, studies of human liver samples revealed MCP-1 gene expression in nondiseased liver and greatly increased levels in livers from patients with fulminant hepatic failure. These data implicate MCP-1 from fat-storing cells as a modulator of the process of liver injury and further support a role for MCP-1 in the pathogenesis of human disease.
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PMID:Monocyte chemoattractant protein 1 (MCP-1) expression occurs in toxic rat liver injury and human liver disease. 828 36

The chemokine monocyte chemoattractant protein 1 (MCP-1) is produced predominantly by mononuclear phagocytes and stimulates recruitment into infected tissues of blood monocytes and T cells. These cell types are thought to be critical to host defenses against infections due to Cryptococcus neoformans, a major cause of disease in persons with AIDS and other disorders of cell-mediated immunity. Accordingly, in the present study, we examined the conditions under which human monocytes and bronchoalveolar macrophages (BAM) are stimulated by C. neoformans to produce MCP-1. C. neoformans was a potent inducer of MCP-1 release from monocytes, with levels of chemokine secreted similar to that seen following stimulation with lipopolysaccharide (LPS). BAM, in contrast, were stimulated by LPS, but not by C. neoformans, to secrete MCP-1. A peak in MCP-1 mRNA was seen 8 h following cryptococcal stimulation of monocytes. Nine strains of C. neoformans stimulated monocytes to release MCP-1, and there was only modest variation between strains. However, when an individual strain was used, the capacity of C. neoformans to stimulate monocyte MCP-1 release did vary, depending upon the conditions used to grow the fungal stimuli. Finally, C. neoformans stimulated comparable quantities of MCP-1 release in monocytes from donors with and without human immunodeficiency virus infection. These data establish C. neoformans as a potent stimulator of MCP-1 in monocytes, but not in BAM. The failure of C. neoformans to stimulate MCP-1 in BAM, if occurring in vivo, could result in a diminished cell-mediated inflammatory response following inhalation of airborne fungi.
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PMID:Variables affecting production of monocyte chemotactic factor 1 from human leukocytes stimulated with Cryptococcus neoformans. 903 95

Caprine arthritis encephalitis virus (CAEV) is a lentivirus of goats that leads to chronic mononuclear infiltration of various tissues, in particular, the radiocarpal joints. Cells of the monocyte/macrophage lineage are the major host cells of CAEV in vivo. We have shown that infection of cultured goat macrophages with CAEV results in an alteration of cytokine expression in vitro. Constitutive expression of interleukin 8 (IL-8) and monocyte chemoattractant protein 1 (MCP-1) was increased in infected macrophages, whereas transforming growth factor beta1 (TGF-beta1) mRNA was down-regulated. When macrophages were infected with a CAEV clone lacking the trans-acting nuclear regulatory gene tat, IL-8 and MCP-1 were also increased. No significant differences from cells infected with the wild-type clone were observed, suggesting that Tat is not required for the increased expression of IL-8 and MCP-1 in infected macrophages. Furthermore, infection with CAEV led to an altered pattern of cytokine expression in response to lipopolysaccharide (LPS), heat-killed Listeria monocytogenes plus gamma interferon, or fixed cells of Staphylococcus aureus Cowan I. In infected macrophages, tumor necrosis factor alpha, IL-1beta, IL-6, and IL-12 p40 mRNA expression was reduced in response to all stimuli tested whereas changes in expression of granulocyte-macrophage colony-stimulating factor depended on the stimulating agent. Electrophoretic mobility shift assays demonstrated that, in contrast to effects of human immunodeficiency virus infection of macrophages, CAEV infection had no effect on the level of constitutive nuclear factor-kappaB (NF-kappaB) activity or on the level of LPS-stimulated NF-kappaB activity, suggesting that NF-kappaB is not involved in altered regulation of cytokine expression in CAEV-infected cells. In contrast, activator protein 1 (AP-1) binding activity was decreased in infected macrophages. These data show that CAEV infection may result in a dysregulation of expression of cytokines in macrophages. This finding suggests that CAEV may modulate the accessory functions of infected macrophages and the antiviral immune response in vivo.
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PMID:Caprine arthritis encephalitis virus dysregulates the expression of cytokines in macrophages. 931 28

This study demonstrates that the therapeutic effect of a nitric oxide inhibitor in a murine model of fecal peritonitis is mediated in part by increased levels of interleukin-10 (IL-10) and monocyte chemoattractant protein 1 (MCP-1). Female CD1 mice were subjected to cecal ligation and puncture (CLP) with a 21-gauge needle and, immediately following surgery, were injected intraperitoneally with saline, N(G)-nitro-L-arginine methyl ester (L-NAME; 8 mg/kg), or N(G)-nitro-D-arginine methyl ester (D-NAME; 8 mg/kg). At 96 h after surgery and drug treatment, 20% of mice that received D-NAME had survived whereas 60% of mice that received L-NAME were alive. To elucidate the effect of L-NAME treatment on chemokine and cytokine production during fecal peritonitis, the levels of macrophage inflammatory protein 2 (MIP-2), IL-10, and MCP-1 were measured in peritoneal washings from additional groups of mice 24 h after the CLP surgery. Peritoneal fluids from L-NAME-treated mice contained significantly higher levels of IL-10 and MCP-1 than did those from D-NAME-treated mice. To elucidate the effect of nitric oxide inhibition on potential cellular sources of IL-10 and MCP-1 in the CLP model, cultured alveolar and peritoneal macrophages were activated with bacterial lipopolysaccharide in the presence of L-NAME; these macrophages produced significantly more MCP-1 than did similarly activated macrophages in the presence of D-NAME. In the CLP surgery model, immunoneutralization of IL-10 alone or IL-10 and MCP-1 together with polyclonal antibodies prior to surgery significantly reduced the survival rates in L-NAME-treated groups compared with L-NAME-treated groups that received preimmune serum. Taken together, these data demonstrate that the inhibition of nitric oxide following experimental CLP fecal peritonitis is therapeutic, in part through the modulatory effect of this treatment on the synthesis of IL-10 and MCP-1.
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PMID:Therapeutic effects of nitric oxide inhibition during experimental fecal peritonitis: role of interleukin-10 and monocyte chemoattractant protein 1. 945 22

Injury in non-neuronal tissues stimulates chemokine expression leading to recruitment of inflammatory cells responsible for orchestration of repair processes. The signals involved in directing repair of damage to the brain are less well understood. We hypothesized that following brain injury, chemokines are expressed and regulate the rate and pattern of inflammatory cell accumulation. The two chemokine subfamilies are alpha(alpha)-chemokines, which primarily function as neutrophil chemoattractants, and the beta(beta)-chemokines, which function primarily as monocyte chemoattractants. We assessed alpha and beta chemokine mRNA expression patterns and leukocyte accumulation following a cerebral cortical lesion. Cortical lesions were produced with and without addition of endotoxin, Escherichia coli lipopolysaccharide (LPS), which stimulates cytokine expression. We studied the expression of the beta-chemokines: monocyte chemoattractant protein (gene product JE; MCP-1/JE), macrophage inflammatory protein-1 alpha and beta (MIP-1alpha and MIP-1beta), and the regulated upon activation normal T expressed and secreted chemokine (RANTES) as well as the alpha-chemokines: interferon-gamma-inducible protein (IP-10) and N51/KC (KC; a murine homologue of MIP-2). Changes in gene expression were analyzed by Northern analysis at different time points following injury. Leukocyte and macrophage densities were analyzed by immunohistochemistry at the same time intervals. All chemokines were elevated following cortical injury/endotoxin. MCP-1 and MIP-1alpha were elevated at 2 h and peaked 6 h, MIP-1beta peaked at 6 h, but declined more rapidly than MCP-1 or MIP-1alpha, and IP-10 peaked at 6 h and showed the most rapid decline. KC was elevated at 1 h, and peaked at 6 h following LPS. RANTES was elevated at 1 h and achieved a plateau level between 6 and 18 h, then declined. In contrast, sterile injuries produced in the absence of endotoxin only induced the mRNA of the beta-chemokine MCP-1, and its expression was delayed compared to the cortical injury/endotoxin group. The presence of chemokine message as early as 1 h indicates that expression of this class of molecules is an early response in the repair process following traumatic brain injury. Macrophage/microglia accumulation occurred more rapidly, activated microglia further from the lesion border, and more cells accumulated in cortical injury/endotoxin than in cortical lesions produced under sterile conditions. Thus, there was a positive correlation between beta-chemokine expression and the number of beta-chemokine responsive cells (i.e. microglia) accumulating in injury sites. This is the first comprehensive study using a panel of chemokine probes and specific marcophage/microglial markers to study in vivo activation of the brain following injury. Our data show that the brain is capable of expression of multiple chemokine genes upon appropriate stimulation (e.g. LPS-treatment). The gradient of microglial activation is consistent with physical damage stimulating release of chemokines that diffuse from the injury site. These data strongly suggest that chemokines are instrumental in the initiation of repair processes following brain injury.
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PMID:Selective chemokine mRNA expression following brain injury. 955 51

C/EBPepsilon is a member of the CCAAT/enhancer binding protein family of basic region/leucine zipper transcriptional activators. The C/EBPepsilon protein is highly conserved between rodents and humans, and its domain structure is very similar to C/EBPalpha. In mice C/EBPepsilon mRNA is only detected in hematopoietic tissues, including embryonic liver and adult bone marrow and spleen. Within the hematopoietic system, C/EBPepsilon is expressed primarily in myeloid cells, including promyelocytes, myelomonocytes, and their differentiated progeny. To identify potential functions of C/EBPepsilon, cell lines over-expressing the C/EBPepsilon protein were generated in the P388 lymphoblastic cell line. In contrast to the parental cell line, C/EBPepsilon-expressing cell lines displayed lipopolysaccharide-inducible expression of the interleukin-6 and monocyte chemoattractant protein 1 (MCP-1) genes as well as elevated basal expression of the MIP-1alpha and MIP-1beta chemokine genes. In the EML-C1 hematopoietic stem cell line, C/EBPepsilon mRNA levels increased as the cells progressed along the myeloid lineage, just preceding activation of the gene encoding the receptor for macrophage-colony-stimulating factor (M-CSFR). M-CSFR expression was stimulated in C/EBPepsilon-expressing P388 cell lines, when compared with either the parental P388 cells or P388 cell lines expressing either C/EBPalpha or C/EBPbeta. These results suggest that C/EBPepsilon may be an important regulator of differentiation of a subset of myeloid cell types and may also participate in the regulation of cytokine gene expression in mature cells.
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PMID:C/EBPepsilon is a myeloid-specific activator of cytokine, chemokine, and macrophage-colony-stimulating factor receptor genes. 959 84

Macrophages are a major source of proinflammatory cytokines such as tumor necrosis factor alpha (TNF-alpha), which are expressed during conditions of inflammation, infection, or injury. We identified an activity secreted by a macrophage tumor cell line that negatively regulates bacterial lipopolysaccharide (LPS)-induced expression of TNF-alpha. This activity, termed TNF-alpha-inhibiting factor (TIF), suppressed the induction of TNF-alpha expression in macrophages, whereas induction of three other proinflammatory cytokines (interleukin-1beta [IL-1beta], IL-6, and monocyte chemoattractant protein 1) was accelerated or enhanced. A similar or identical inhibitory activity was secreted by IC-21 macrophages following LPS stimulation. Inhibition of TNF-alpha expression by macrophage conditioned medium was associated with selective induction of the NF-kappaB p50 subunit. Hyperinduction of p50 occurred with delayed kinetics in LPS-stimulated macrophages but not in fibroblasts. Overexpression of p50 blocked LPS-induced transcription from a TNF-alpha promoter reporter construct, showing that this transcription factor is an inhibitor of the TNF-alpha gene. Repression of the TNF-alpha promoter by TIF required a distal region that includes three NF-kappaB binding sites with preferential affinity for p50 homodimers. Thus, the selective repression of the TNF-alpha promoter by TIF may be explained by the specific binding of inhibitory p50 homodimers. We propose that TIF serves as a negative autocrine signal to attenuate TNF-alpha expression in activated macrophages. TIF is distinct from the known TNF-alpha-inhibiting factors IL-4, IL-10, and transforming growth factor beta and may represent a novel cytokine.
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PMID:Tumor necrosis factor alpha transcription in macrophages is attenuated by an autocrine factor that preferentially induces NF-kappaB p50. 974 85

Astrocytes constitute a part of the blood-brain barrier. Chemokine expression by astrocytes may contribute to leucocyte infiltration within the central nervous system (CNS) during inflammation. To investigate factor(s) regulating chemokine expression by astrocytes, we studied the induction of beta-chemokine mRNA expression in adult rat astrocytes. Astrocyte-derived monocyte chemoattractant protein- (MCP-1), RANTES, macrophage inflammatory protein (MIP)-1alpha and MIP-1beta mRNA were induced by interferon-gamma (IFN-gamma). Tumour necrosis factor-alpha (TNF-alpha) induced MCP-1, RANTES and MIP-1beta mRNA expression, and lipopolysaccharide (LPS) induced MCP-1, MIP-1alpha and MIP-1beta mRNA expression in astrocytes. LPS-induced MCP-1, MIP-1alpha and MIP-1beta mRNA expression by astrocytes was antagonized by transforming growth factor (TGF)-beta1 and interleukin (IL)-10. TGF-beta1 and IL-10 also down-regulated MCP-1 and RANTES mRNA expression induced by TNF-alpha. IL-10, but not TGF-beta1, inhibited MIP-1beta mRNA expression induced by TNF-alpha. The results of this in vitro study suggest that beta-chemokine mRNA expression by adult rat astrocytes can be induced by LPS or proinflammatory cytokines, while regulatory cytokines, such as TGF-beta1 and IL-10, down-regulate astrocyte-derived beta-family chemokine mRNA expression induced by LPS, IFN-gamma and TNF-alpha. Further study of CNS chemokines will enhance our understanding of leucocyte recruitment to the CNS and suggest therapeutic strategies for neurological disorders.
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PMID:Regulation of beta-chemokine mRNA expression in adult rat astrocytes by lipopolysaccharide, proinflammatory and immunoregulatory cytokines. 982 59

Gut-derived lipopolysaccharide (LPS) may contribute to hepatocellular necrosis in alcoholic hepatitis through neutrophil sequestration in hepatic sinusoids. It is well known that the female has a greater susceptibility to alcoholic liver injury than the male. The aim of the present study was to investigate the effect of long-term ethanol consumption on ability of the liver to produce cytokine-induced neutrophil chemoattractant-1 (CINC-1), the most potent neutrophil-chemokine in rats, after LPS administration. Furthermore, we aimed to evaluate the gender difference in this ability. Male and female rats were pair-fed a liquid diet containing 36% of the total calories as ethanol or dextrose for 6 to 8 weeks. They were given LPS intravenously, and chemokine mRNA expression in the liver was evaluated after 2 and 6 hr. To study the organ or chemokine specificity, CINC-1 mRNA expression in the spleen and monocyte chemoattractant protein (MCP)-1 mRNA level were also determined. Serum ALT activity started to increase between 2 and 6 hr. Female rats fed an ethanol diet showed significantly higher ALT activity 6 hr after LPS injection than the male rats. CINC-1 mRNA expressions in the liver after 2 and 6 hr were significantly higher in the ethanol-fed group, compared with the pair-fed control. Female rats fed an ethanol diet showed a significantly higher level of CINC-1 mRNA in the liver than the male rats 2 hr after LPS injection. CINC-1 levels in the liver homogenates paralleled closely its mRNA expression, whereas its concentrations in sera did not correlate with those in the liver. Neither CINC-1 mRNA expression in the spleen nor MCP-1 mRNA expression in the liver was affected by ethanol feeding or gender. An additional experiment using the gonadectomized rats fed an ethanol diet showed that gonadectomy totally abolished the gender difference in CINC-1 mRNA of the liver. We conclude that CINC-1 induction in the liver may be responsible for LPS-induced hepatitis in the ethanol-fed rats, and that the difference in ability to produce CINC-1 between males and females is one important factor that may partly account for the gender difference of alcoholic liver disease.
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PMID:Effect of long-term ethanol consumption on ability to produce cytokine-induced neutrophil chemoattractant-1 in the rat liver and its gender difference. 1023 81

The recruitment of immunocompetent cells to the site of inflammation represents an essential part of the host defense during continuous ambulatory peritoneal dialysis (CAPD)-related peritonitis. Recently, it was shown that intraperitoneal application of granulocyte macrophage-colony stimulating factor (GM-CSF) leads to a marked transient recruitment of macrophages, paralleled by an increase in monocyte chemoattractant protein (MCP)-1. We, therefore, tested the in vitro effect of GM-CSF on the release of the chemotaxins interleukin (IL)-8 and MCP-1 by human peritoneal macrophages. Cells were stimulated with recombinant GM-CSF for 4, 12, and 20 hours in concentrations ranging from 0.1 to 100 pg/mL. Cells stimulated with lipopolysaccharide (LPS) or unstimulated cells served as control. Recombinant GM-CSF at concentrations found during CAPD peritonitis in vivo significantly increased the release of IL-8 and MCP-1 in a time- and dose-dependent manner. The maximum effect of IL-8 was observed directly after cell isolation, and decreased after a culture period of 10 days. Thus, our results indicate that peritoneal macrophages are the potential source of chemokines released upon GM-CSF stimulation.
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PMID:Granulocyte macrophage-colony stimulating factor stimulates secretion of chemoattractive cytokines by peritoneal macrophages of CAPD patients. 1064 17


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