Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P30536 (PBS)
 9,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. When injected into a 6-day-old mouse air-pouch, human recombinant interleukin-8 (IL-8; 0.03-3 micrograms) induced, in a dose-dependent fashion, an accumulation of neutrophils which could be reliably assessed 4 h after the injection. No protein extravasation was measured above the values obtained with the vehicle alone (carboxymethylcellulose, CMC, 0.5% w/v in phosphate-buffered solution, PBS). 2. The IL-8 effect (routinely evaluated at 1 microgram dose) was inhibited neither by local administration of actinomycin D (1 microgram) nor by systemic treatment with indomethacin (1 mg kg-1, i.v.), BWA4C (5 mg kg-1, p.o.), methysergide (6 mg kg-1, i.p.) and RP67580 (2 mg kg-1, i.p.). 3. Treatment of mice with the H1 antagonist, mepyramine (1-10 mg kg-1, i.p.) resulted in a dose-dependent inhibition of the cell accumulation elicited by the chemokine, with a maximal reduction of approximately 50-60%. The mepyramine effect was not due to a non specific reduction of neutrophil function, since treatment with this drug (6 mg kg-1, i.p.) did not modify the cell infiltration measured in response to a challenge with interleukin-1 beta (20 ng) or with the vehicle CMC to any extent. Moreover, treatment of mice with mepyramine did not modify cell counts in a peripheral blood film with respect to controls. Two other H1 antagonists, chemically unrelated to mepyramine, diphenhydramine (9 mg kg-1, i.p.) and triprolidine (0.5 mg kg-1, i.p.), inhibited IL-8-induced migration to a similar extent (approximately 50-60%), whereas the H2 antagonist, ranitidine (5 mg kg-1, i.p.) was without effect. 4. The concept that endogenous histamine could be involved in the IL-8 effect was strengthened in two ways: (i) addition of histamine (0.2-2 microg) to a small dose of IL-8 (0.3 microg) potentiated the cell elicitation induced by the chemokine without having any effect on its own; (ii) IL-8-induced neutrophil accumulation was greatly impaired in animals depleted of mast cell amines by sub-chronic (5 day) treatment with compound 48/80 according to an established protocol.5. The glucocorticoid dexamethasone (Dex; 1-50 microg per mouse, i.v., corresponding approximately to 0.03-1.5 mg kg-1, given i.v. 2 h prior to challenge with IL-8) potently inhibited neutrophil infiltration with an approximate ED50 of 5 microg per mouse (~ 0.3 mg kg-1 , i.v.). Passive immunisation of mice with a polyclonal sheep serum raised against the steroid-inducible anti-inflammatory protein lipocortin 1 (LCl)abolished the inhibitory action of Dex whereas a control serum was without effect.6. Local administration of Dex at a dose which was ineffective when given systemically (1 microg) also reduced neutrophil migration induced by IL-8, either alone or in combination with histamine. This local inhibition (~50%), also seen with hydrocortisone (30 microg), was prevented by the concomitant administration of the steroid antagonist RU38486 (10 microg) indicating the involvement of glucocorticoid receptor in the response.7. These findings characterize further the mechanisms underlying PMN recruitment induced by IL-8 in vivo, and point to a role for histamine. The anti-inflammatory action of the glucocorticoids, as in some other models, appears to be LCl-dependent when these drugs are given systemically and LCl independent when the steroids are given locally.
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PMID:A role for endogenous histamine in interleukin-8-induced neutrophil infiltration into mouse air-pouch: investigation of the modulatory action of systemic and local dexamethasone. 752 59

Previous studies from this laboratory have demonstrated that the chemokines RANTES (recombinant human regulated upon activation, normally T cell expressed and presumably secreted), macrophage chemotactic peptide-1, recombinant human macrophage inflammatory protein-1 alpha (rhMIP-1 alpha) IL-8, and IP-10 are capable of inducing human T cell infiltration into the injection site of severe combined immunodeficiency (SCID) mice reconstituted with human PBL. However, the ability of these chemokines to facilitate T cell homing into various lymphoid tissues has not been examined. Initial studies focused on the ability of rhMIP-1 beta to induce human T cell infiltration into injection sites in human PBL-SCID mice. SCID mice received s.c. injections of rhMIP-1 beta or PBS (1 microgram/injection) in the hindflank for 4 h or sequential injections for 3 days. Biopsies of the MIP-1 beta injection site revealed the presence of significant mononuclear cell accumulation 72 h after injection. Immunohistologic evaluation determined that significant numbers of human CD3+ T cells were recruited in response to MIP-1 beta injections, and this infiltration could be specifically blocked by co-administration of anti-MIP-1 beta antiserum. We subsequently examined these chemokine-injected mice for the effect of trafficking of human T cells to peripheral lymphoid organs. Flow cytometric analysis of the thymus in human PBL-SCID mice revealed that treatment with rhMIP-1 beta or rhRANTES, but not platelet factor-4, resulted in improved thymic homing of the human T cells after 72 h. This trafficking effect was shown to be direct, as pretreatment of the human T cells with the chemokines in vitro also improved peripheral lymphoid trafficking of the human cells. In addition, co-injection of rhMIP-1 beta with anti-1 beta antiserum abrogated the increase in T cell homing to the thymus. These data demonstrate that MIP-1 beta and RANTES directly augment human T cell trafficking to peripheral murine lymphoid tissues. Chemokines may, therefore, under either isogeneic or xenogeneic conditions, play a role in normal lymphocyte recirculation and homing, and may be of potential clinical use in promoting immune cell trafficking and function.
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PMID:Chemokines and T lymphocyte activation: II. Facilitation of human T cell trafficking in severe combined immunodeficiency mice. 869 Aug 98

Chemokines may control mast cell infiltrates found in many inflammatory diseases. These cells act through at least two main functions: migration and degranulation. Here we show that human recombinant monocyte chemotactic protein (MCP)-1 (10 ng/50 microliters) induces, after 4 h, an inflammatory vascular permeability and cellular extravasation reaction, determined by Evan's blue dye (1% in saline) injected into the tail vein of the rat, when injected intradermally in the rat skin. The blue color accumulating at the sites of injection provides evidence of vascular permeability and cellular extravasation. The colored areas of the skin were then enucleated and immersed in a fixative solution. Slides were prepared with sections of tissue colored with toluldine blue and analyzed under an optical microscope. A significant number of basophilic cells migrated to the injected area where MCP-1 (10 ng/50 microliters) was used compared to the control PBS treatment. Cell recruitment was slightly less than N-formyl-methionine-leucyl-phenylalanine (used at 10(-6) M/50 microliters). Electron microscopy studies confirmed the presence of basophilic granular cells where MCP-1 was intradermally injected. After preparation of a histidine decarboxylase (HDC) probe, a Northern blot analysis was determined for HDC mRNA in the enucleated tissue injected with MCP-1 (10 ng/50 microliters). Steady-state levels of HDC mRNA levels were induced after 4 h. These results were confirmed by the higher amount of histamine release, compared to the control PBS, in the enucleated tissue from the MCP-1 injection sites. Our results suggest that MCP-1 could play a significant role in diseases characterized by basophilic cell accumulation and migration to sites of tissue damage. Moreover, we show for the first time that MCP-1 is a pro-inflammatory chemokine that induces basophilic cell migration in rat skin injection sites.
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PMID:Monocyte chemotactic protein-1 is a proinflammatory chemokine in rat skin injection sites and chemoattracts basophilic granular cells. 935 62

RANTES (regulated upon activation normal T expressed and secreted) is another member of the intercrine beta subfamily which acts as a selective chemoattractant for human monocytes and CD4-positive lymphocytes and increases the adherence of monocytes to endothelial cells. In this work, the effect of RANTES was studied on rat skin injection sites. Rats were intradermally injected with 50 microliters of RANTES, at different concentrations, fMet-Leu-Phe (FMLP), or LPS (positive controls) or PBS vehicle (negative control). The animals were then injected with 0.6 ml of Evans' blue in the tail vein in order to obtain a blue colour in the areas where the compounds were injected. After 4 h the rats were killed and the maximum diameter of the blue extravasation area was measured. The coloured areas were then excised and optical and electron microscopic studies were performed. In addition, in some of the excised tissue, a Northern blot analysis for histidine decarboxylase (HDC) mRNA was performed along with an estimation of the amount of histamine generated in the tissue injection sites. In these studies it was found that intradermal injections of 5, 2.5, and 1.25 x 10(-5) M RANTES produced a strong inflammatory response with the accumulation of a great number of basophil cells compared with the PBS (50 microliters) negative control, or FMLP (10(-6) M/50 microliters) or LPS (10 ng/50 microliters) positive control, after 4 h. Moreover, 5, 2.5, 1.25 x 10(-5) M RANTES produced a dose-response stimulation of HDC mRNA in the tissues of skin injection sites. The increasing number of basophils in the RANTES inflamed tissues led to augmentation of histamine content, compared with the PBS control. In conclusion, the pro-inflammatory chemokine RANTES stimulates the generation of HDC mRNA in skin injection sites.
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PMID:RANTES is a pro-inflammatory chemokine and chemoattracts basophil cells to extravascular sites. 942 93

RANTES (regulated upon activation, normal T cell expressed and presumably secreted) and other chemoattractant proteins are members of the intercrine or chemokine family of proinflammatory basic polypeptides. RANTES is a prototype of the C-C chemokine subfamily that acts as a selective chemoattractant for human monocytes and CD4-positive lymphocytes and increases the adherence of monocytes to endothelial cells. However, the role of RANTES in white cells is still unclear. We report here that hrRANTES at 20 ng/50 microl in mice causes mast cell recruitment 4 h after intramuscular injection, an effect inhibited by anti-RANTES, as evidenced by 0.1% Toluidine blue, a specific dye for coloring mast cells. Injections of PBS (50 microl) vehicle (negative control) did not produce any appreciable inflammatory response, whereas injection of lipopolysaccharide 20 ng/50 microl (positive control) generated a marked inflammatory state. When RANTES was injected intramuscularly in genetically mast cell-deficient W/Wv mice, the inflammatory effect was not present. The RANTES injection sites were then excised and studied under an optical and electron microscope. A Northern blot analysis was performed using a probe that was prepared to detect mRNA encoding the histidine decarboxylase (HDC) gene on excised muscle tissue. We found that hrRANTES provoked generation of HDC mRNA from muscle tissue after 4 h. These effects were inhibited by an anti-RANTES antibody and were absent in genetically mast cell-deficient mice. The increasing number of mast cells in the RANTES injection sites led to an augmentation of histamine content compared to controls (PBS). The injection of hrRANTES 20 ng/20 microl into the sole of a rat paw confirmed the inflammatory and the mast cell recruitment potential of this chemokine. In these studies, hrRANTES injections in muscle tissue provided direct in vivo evidence that RANTES has a significant effect on mast cell recruitment and HDC mRNA generation.
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PMID:Intramuscular injection of hrRANTES causes mast cell recruitment and increased transcription of histidine decarboxylase in mice: lack of effects in genetically mast cell-deficient W/WV mice. 983 59

Infection of C57BL/6 mice with mouse hepatitis virus strain V5A13.1 (MHV-V5A13.1) results in an acute encephalitis followed by a chronic, progressive demyelinating disease with clinical and histological similarities to the human demyelinating disease Multiple Sclerosis (MS). Studies were undertaken to evaluate the contribution of NOS2 generated NO in demyelination in MHV-infected mice. MHV-infected animals were treated daily with either 8 mg of aminoguanidine (AG), a selective inhibitor of NOS2 activity, or PBS by intraperitoneal (i.p.) injection. MHV-infection of mice resulted in 20% mortality in both groups with surviving mice clearing virus below levels of detection, as measured by plaque assay, by day 12 postinfection (p.i.). A significant decrease in the severity of clinical disease was observed in AG-treated animals as compared to mice receiving PBS at days 7 and 12 p.i. (P< or =0.001 and 0.003, respectively) however, by day 21 p.i. AG-treated mice exhibited the same severity of clinical disease as control animals. Examination of brain and spinal cords from infected mice revealed a pronounced reduction in the severity of inflammation at day 7 p.i. in mice treated with AG as compared to control mice. By day 12 p.i. there was a significant decrease (P< or =0.02) in the severity of demyelination in AG-treated mice as compared to control animals yet both PBS and AG treated mice had a similar degree of demyelination by day 21 p.i. Analysis of chemokine mRNA transcripts by RNase protection assay revealed that AG-treated mice had significantly lower levels (P < or = 0.007) of transcripts for the C-C chemokine monocyte chemoattractant protein-1 (MCP-1) at day 7 p.i. as compared to control animals. By day 12 p.i., AG-treated mice and control mice had similar levels of chemokine transcripts. Together, these data suggest that inhibition of NOS2/NO slows the progression of MHV-induced demyelination. One potential mechanism by which this may occur is through controlling inflammation through modulation of chemokine expression in the CNS.
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PMID:Inhibition of nitric oxide synthase-2 reduces the severity of mouse hepatitis virus-induced demyelination: implications for NOS2/NO regulation of chemokine expression and inflammation. 1019 Jun 90

We examined the mechanisms involved in the development of lung lesions after infection with Cryptococcus neoformans by comparing the histopathological findings and chemokine responses in the lungs of mice infected with C. neoformans and assessed the effect of interleukin (IL) 12 which protects mice from lethal infection. In mice infected intratracheally with a highly virulent strain of C. neoformans, the yeast cells multiplied quickly in the alveolar spaces but only a poor cellular inflammatory response was observed throughout the course of infection. Very little or no production of chemokines, including MCP-1, RANTES, MIP-1alpha, MIP-1beta and IP-10, was detected at the mRNA level using RT-PCR as well as at a protein level in MCP-1, RANTES and MIP-1alpha. In contrast, intraperitoneal administration of IL-12 induced the synthesis of these chemokines and a marked cellular inflammatory response involving histiocytes and lymphocytes in infected mice. Our findings were confirmed by flow cytometry of intraparenchymal leukocytes obtained from lung homogenates which showed IL-12-induced accumulation of inflammatory cells consisting mostly of macrophages and CD4+ alphabeta T cells. On the other hand, C-X-C chemokines including MIP-2 and KC, which attract neutrophils, were produced in infected and PBS-treated mice but treatment with IL-12 showed a marginal effect on their level, and neutrophil accumulation was similar in PBS- and IL-12-treated mice infected with C. neoforman. Our results demonstrate a close correlation between chemokine levels and development of lung lesions, and suggest that the induction of chemokine synthesis may be one of the mechanisms of IL-12-induced protection against cryptococcal infection.
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PMID:Chemokine responses and accumulation of inflammatory cells in the lungs of mice infected with highly virulent Cryptococcus neoformans: effects of interleukin-12. 1049 71

Product R (Reticulose(TM)) is a peptide-nucleic acid immunomodulator with broad-spectrum antiviral activity that was recently shown to increase expression of mRNAs encoding the proinflammatory cytokines, IFN-gamma, IL-1beta, IL-6 and TNF-alpha. Since these cytokines induce expression of the chemokines, MIP-1alpha, MIP-1beta, RANTES, and SDF-1, all of which inhibit viral infectivity, we were interested to determine if Product R also alters chemokine expression. In addition, the finding, that Product R decreases HIV-1 RNA and extracellular p24 antigen in H9 T-lymphoma cells, suggested to us that this drug may block viral infection by reducing the expression of chemokine receptors on target cells. We have therefore utilized H9 cells to test the effects of Product R on expression of mRNAs encoding the chemokine receptors, CD4, CXCR4 and CCR5, as well as their ligands, IL-16, SDF-1, MIP-1alpha, MIP-1beta, and RANTES, by RT-PCR. We also assayed the effect of Product R on surface receptor expression by flow cytometry, and on the chemotactic activity of these cells towards the CXCR4 ligand, SDF-1, and the CCR5 ligands, MIP-1alpha and RANTES. H9 cells were cultured for 3-21 days in medium containing 5% or 10% Product R, or 5% or 10% PBS. We found that, compared to control cultures, cells cultured in media containing Product R expressed lower amounts of CXCR4 and CCR5 mRNA and surface antigen at all time points. Culture for 3 days in media containing Product R also reduced the ability of cells to migrate towards 10-20 ng/ml SDF-1 and 100-250 ng/ml RANTES. In contrast, Product R had no effect on the expression of CD4 mRNA and receptor protein, or on expression of IL-16 mRNA. These findings suggest that Product R may have clinical efficacy in HIV-1-infected patients by downregulating viral coreceptors on target T-cells.
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PMID:CXCR4 and CCR5 expression by H9 T-cells is downregulated by a peptide-nucleic acid immunomodulator. 1106 99

The chemokine stroma-derived factor (SDF)-1, and its receptor, CXCR-4, have been shown to be essential for the translocation of hemopoietic stem cells from the fetal liver to the bone marrow (BM). We hypothesized that if CXCR-4 plays a crucial role in the localization of human hemopoiesis, stem cells from distinct tissue sources should demonstrate distinct CXCR-4 expression or signaling profiles. CD34(+) cells from BM were compared with blood: either mobilized peripheral blood or umbilical cord blood. Unexpectedly, significantly higher levels of CXCR-4 surface expression on CD34(+) cells from blood sources, mobilized peripheral blood, or cord blood were observed compared with BM (p = 0.0005 and p = 0.002, respectively). However, despite lower levels of CXCR-4, responsiveness of the cells to SDF-1 as measured by either calcium flux or transmigration was proportionally greatest in cells derived from BM. Further, internalization of CXCR-4 in response to ligand, associated with receptor desensitization, was significantly lower on BM-derived cells. Therefore, preserved chemokine receptor signaling was highly associated with marrow rather than blood localization. To test the functional effects of perturbing CXCR-4 signaling, adult mice were exposed to the methionine-SDF-1beta analog that induces prolonged down-regulation/desensitization of CXCR-4 and observed mobilization of Lin(-), Sca-1(+), Thy-1(low), and c-kit(+) hemopoietic progenitor cells to the peripheral blood with a >30-fold increase compared with PBS control (p = 0.0007 day 1 and p = 0.004 day 2). These data demonstrate that CXCR-4 expression and function can be dissociated in progenitor cells and that desensitization of CXCR-4 induces stem cell entry into the circulation.
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PMID:CXCR-4 desensitization is associated with tissue localization of hemopoietic progenitor cells. 1129 Jul 83

The role of selectins in neutrophil emigration in response to the CXC chemokines KC and MIP-2 was investigated in wild type and P-selectin deficient mice. Intrapleural injection of KC or MIP-2 induced a rapid and specific neutrophil accumulation. Emigration 2 h after KC or MIP-2 was reduced 83 - 88% by anti-L-selectin mAb and 53 - 63% by anti-P-selectin mAb. Co-administration of anti-L- and P-selectin mAbs abolished neutrophil migration induced by either chemokine. An anti-E-selectin mAb tested alone did not affect KC-induced neutrophil migration after 2 or 4 h. Moreover, anti-E-selectin did not have an additive inhibitory effect on KC-induced neutrophil migration compared with P-selectin blockade alone. This was found when neutrophil migration was measured at 2 and 4 h after KC. Despite a blood neutrophilia, neutrophil migration at 2 and 4 h after KC was markedly smaller (by approximately 90%) in P-selectin deficient mice compared with wild type animals. Responses at both time points were not decreased further in animals given E-selectin mAb but were reduced to the PBS control level in the presence of anti-L-selectin. In vitro study of cultured murine endothelial cells demonstrated that KC can directly increase cell surface P-selectin expression. These data suggest that CXC chemokine-induced neutrophil accumulation is dependent on both neutrophil L-selectin and a rapid upregulation of endothelial P-selectin but there is no evidence for E-selectin induction.
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PMID:Dominant role of L- and P-selectin in mediating CXC chemokine-induced neutrophil migration in vivo. 1139 72


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