Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10145 (IL-8)
 23,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To test the hypothesis that mesothelial cells play a role in regulating inflammatory responses within the pleural space, we examined neutrophil chemotactic activity released by cytokine-stimulated mesothelial cells. Human mesothelial cells were isolated from patients with transudative pleural effusions and cultured. The purity of the cell population was assessed by morphologic, immunocytochemical, and biochemical characteristics. Confluent fourth passage mesothelial cell plates were exposed to varying concentrations of the recombinant human cytokines IL-1 alpha, TNF-alpha, or IFN-gamma, or Escherichia coli endotoxin (LPS). Polymorphonuclear neutrophil (PMN) chemotactic activity in the conditioned media was measured in microchemotaxis chambers. Although none of the cytokines demonstrated inherent chemotactic activity, each stimulated mesothelial cells to produce PMN chemotactic activity in a dose-dependent manner. TNF-alpha stimulated the release of the greatest quantity, whereas stimulation with IFN-gamma and IL-1 alpha resulted in the release of lesser but still significant quantities of PMN chemotactic activity. By contrast, LPS did not increase the basal level of chemotactic activity produced by the cells. The cytokine-induced chemotactic activity was proteinaceous, required de novo synthesis, and had a predominant m.w. of 10,000. Significant quantities of immunoreactive neutrophil-activating peptide-1 (NAP-1)/IL-8 were detected in mesothelial cell supernatants after stimulation with each of the cytokines. The neutrophil chemotactic activity of supernatants from mesothelial cells stimulated with either IL-1 alpha or IFN-gamma was completely neutralized with rabbit anti-human NAP-1/IL-8 polyclonal antiserum. The same antiserum neutralized the majority, but not all, of the neutrophil chemotactic activity in supernatants from TNF-stimulated mesothelial cells. Stimulated mesothelial cells also expressed an inducible mRNA transcript that hybridized with a specific oligonucleotide probe for human NAP-1/IL-8. These observations provide a mechanism whereby mesothelial cells could respond to inflammatory stimuli in the underlying lung and regulate inflammatory responses within the pleural space.
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PMID:Cytokine-stimulated human mesothelial cells produce chemotactic activity for neutrophils including NAP-1/IL-8. 130 57

Lipid X, a monosaccharide precursor of the lipid A component of LPS, has been found to antagonize LPS-induced priming of human neutrophils in a manner consistent with competitive inhibition. In this investigation, the inhibition of neutrophil priming by lipid A analogs was found to be specific for LPS-induced priming. Priming of neutrophils by TNF, IL-8, and C5a were all unaffected by increasing concentrations of 3-aza-lipid X-4-phosphate (compound 3), a monosaccharide LPS-antagonist. Unlike lipid X, the pattern of antagonism exhibited by some monosaccharide LPS-antagonists was noncompetitive-like. The relationship between the chemical structure and inhibition pattern was found to be complex and not simply related to the type of acyl linkage at the C-3 position of the glucosamine backbone. Lipid A analogs were found to antagonize calcium ionophore A23187-stimulated leukotriene B4 (LTB4) production from LPS-primed neutrophils in a pattern of inhibition qualitatively similar to that seen with FMLP-stimulated O2- production. Resting and FMLP-stimulated (peak) cytosolic-free calcium levels did not differ significantly between unprimed and LPS-primed neutrophils, (p = 0.67 and p = 0.97, respectively). Furthermore, antagonism of LPS-mediated priming by 3-aza-lipid X-4-phosphate (compound 3) could not be explained by changes in intracellular calcium flux despite marked inhibition of O2- production (p less than 0.0001). Thus, lipid A analogs antagonize only LPS-induced priming and the pattern of inhibition is dependent on the chemical structure. Inhibition of LPS-induced priming by lipid A analogs may involve an early step in the signal transduction pathway common to both O2- and LTB4 generation, but independent of intracellular calcium concentration.
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PMID:Antagonism of lipopolysaccharide-induced priming of human neutrophils by lipid A analogs. 131 5

The hydroxyl radical (OH.) scavenger dimethyl sulfoxide (DMSO) was found to dose-dependently inhibit interleukin 8 (IL-8) production in LPS-stimulated human whole blood. At a concentration of 1% (vol/vol), DMSO blocked IL-8 release by approximately 90% in the presence of 1 microgram/ml LPS at a 24-h time point, but did not affect cell viability or reduce the production of tumor necrosis factor (TNF), interleukin 6, or interleukin-1 beta (IL-1 beta). DMSO was found to directly inhibit IL-8 expression at the level of transcription. Furthermore, this effect was not LPS-specific, in that IL-8 production was reduced by DMSO to a similar extent upon stimulation of blood with phytohemagglutinin, aggregated immune complexes, TNF, or IL-1 beta. Other oxygen radical scavengers that have been shown to inhibit OH.-dependent reactions (dimethyl thiourea, thiourea, mannitol, and ethanol) also inhibited IL-8 production. Conversely, addition of H2O2 caused a dose-dependent stimulation of IL-8 release. These results provide evidence that reactive oxygen metabolites play an important role in the regulation of IL-8 production and suggest that reduction of IL-8 release may contribute to the beneficial effects of antioxidants in experimental models of inflammation and ischemia/reperfusion injury.
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PMID:Oxygen radical scavengers selectively inhibit interleukin 8 production in human whole blood. 133 Nov 81

Endotoxin shock is not only the reflexion of Gram-negative focal infection but also the consequence of dysfunction of the intestinal mucous barrier and a decline of the detoxication capacity, in particular of the hepatic mesenchymal phagocytic system during a critical state. Cytokines and the primary LPS complex and its lipid A resp. are of basic importance. They start the release of a large amount of TNF alpha, IL-1, IL-6, IL-8 and other cascades. Acute shock is controlled nowadays more frequently than in the past, however, there is a high risk of a very adverse reaction of remote organs, which is very adverse from the prognostic aspect. A series of laboratory markers has a greater validity than the clinical picture alone. For screening derived markers are used not primary markers. Despite this they provide adequate information. Prophylaxis and treatment include selective bacterial decontamination, or active or passive immunization (PSAEVA, hyperimmune sera), minidoses of dopamine in a continuous infusion, early enteral nutritional intervention, in particular enteral nutrition containing glutamine. Monoclonal and polyclonal antibodies against the LPS complex and cytokines are tested, blocking their receptors or possibly early plasmapheresis. Permanent pillars of therapeutic tactics are still a radical and early elimination of possible infectious foci and targeted administration of antibiotics and maintenance of the perfusion pressure and adequate oxygenation.
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PMID:[New findings in emergency care and resuscitation in patients at risk for endotoxic shock]. 133

The present study was designed to investigate the capacity of human mononuclear phagocytes to produce a cytokine chemotactic for monocytes (monocyte chemotactic protein (MCP), alternative acronyms JE, monocyte chemotactic and activating factor, MCP-1, and tumor-derived chemotactic factor). Human PBMC exposed in vitro to bacterial LPS expressed high levels of MCP transcripts. Monocyte-depleted lymphoid cells were not induced to express MCP by LPS. Percoll-gradient purified monocytes were able to express high levels of MCP transcripts. In an effort to exclude a role of contaminating non-monocytic cells, mononuclear phagocytes were separated by flow cytometry and sorting: CD14+ cells exposed to LPS showed high levels of MCP mRNA. LPS-stimulated monocytes released chemotactic activity for monocytes that could be inhibited by absorption with anti-MCP antibodies. IL-1, TNF, IFN-gamma, granulocyte-macrophage-CSF and, to a lesser extent, macrophage-CSF, as well as inactivated streptococci, also induced MCP gene expression. Actinomycin D experiments indicated that induction of MCP in monocytes was gene transcription-dependent. The protein synthesis inhibitor cycloheximide (Cy) blocked IL-1-, TNF-, or LPS-induced MCP gene expression in monocytes. In contrast, expression of the structurally related chemotactic cytokine IL-8 was superinduced by Cy. Moreover, Cy superinduced MCP gene expression in cells other than monocytes, including endothelial cells, smooth muscle cell and fibrosarcoma cells, indicating different mechanisms of regulation in mononuclear phagocytes vs cells of other lineages. The capacity of cells of the monocyte-macrophage lineage to produce a cytokine that recruits and activates circulating monocytes may be of considerable importance in inflammatory and immunologic reactions. Thus, the mononuclear phagocyte system can autonomously regulate the extravasation and activation of immature elements of the same lineage, a key event in inflammation and immunity.
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PMID:Expression of a monocyte chemotactic cytokine by human mononuclear phagocytes. 137 May 16

NF-IL6 was originally identified as a DNA-binding protein responsible for IL-1-stimulated IL-6 induction. Direct cloning of NF-IL6 revealed its homology with C/EBP. C/EBP is expressed in liver and adipose tissues and is supposed to regulate several hepatocyte- and adipocyte-specific genes. In contrast, NF-IL6 is suppressed in normal tissues, but is rapidly and drastically induced by LPS or inflammatory cytokines such as IL-1, TNF, and IL-6. NF-IL6 can also bind to the regulatory region of various genes including IL-8, G-CSF, IL-1 and immunoglobulin genes. Furthermore, NF-IL6 is shown to be identical to IL-6DBP, a DNA-binding protein responsible for IL-6-mediated induction in acute-phase proteins, demonstrating that NF-IL6 is responsible for the genes regulated by IL-6. These results indicate that NF-IL6 may be a pleiotropic mediator of many inducible genes involved in acute, immune, and inflammatory responses, like NFkB. In this regard, it is noteworthy that both an NF-IL6 binding site and an NFkB binding site are present in the inducible genes such as IL-6, IL-8, and several acute-phase genes. On the other hand, accumulating evidence has revealed that overproduction of IL-6 may be responsible for the pathogenesis and/or several symptoms of a variety of diseases, including autoimmune diseases, malignancies, and viral diseases. At present, the molecular mechanisms of abnormal expression of the IL-6 gene are not known. Recently it has become evident that interplays between viral proteins and cellular proteins play an important role in viral oncogenesis and infection. The fact that NF-IL6 binds to the enhancer core sequences of various viruses strongly suggests a possible relationship of virus infection and IL-6 expression. In fact some evidence (Mahe et al. 1991, Spergel et al. 1992) indicates that NF-IL6 may interact with viral gene enhancers or viral products, although there are no definite data about the involvement of NF-IL6 in viral pathogenesis. Future studies will be required to clarify whether or not the interplay between NF-IL6 and viral infection is responsible for deregulation of the IL-6 gene.
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PMID:IL-6 and NF-IL6 in acute-phase response and viral infection. 138 Apr 88

We have previously reported that cytokine- or LPS-activated human umbilical vein endothelial cell (HUVEC) monolayers secrete IL-8 that can act as a neutrophil-selective adhesion inhibitor. In our study we investigated the mechanisms involved in the leukocyte adhesion inhibitory action of IL-8. The leukocyte adhesion inhibitory effect appears to be mediated by the action of IL-8 on the neutrophil, does not involve down-regulation of relevant endothelial adhesion molecules such as endothelial-leukocyte adhesion molecule-1 or intercellular adhesion molecule-1, and is quantitatively similar in different endothelial activation states that are predominantly endothelial-leukocyte adhesion molecule-1 dependent or intercellular adhesion molecule-1 dependent. In addition to inhibiting the attachment of freshly isolated peripheral blood neutrophils to cytokine-activated HUVEC monolayers, IL-8 also promoted a rapid detachment of tightly adherent neutrophils from activated HUVEC, and abolished neutrophil transendothelial migration. Certain other chemoattractants, including FMLP and C5a, had similar inhibitory actions, indicating IL-8 was not unique in its ability to inhibit various neutrophil-endothelial interactions. In contrast, two other neutrophil agonists 1-0-alkyl-2-acetyl sn-glycero-3-phosphocholine and granulocyte-macrophage-CSF, which, like IL-8, are produced by activated HUVEC, as well as the leukocyte-derived chemoattractant leukotriene B4, exerted minimal inhibitory effects on adhesion. Regardless of their ability to modulate neutrophil-endothelial cell adhesion, all these agents induced altered leukocyte surface expression of functionally important adhesion molecules, including loss of L-selectin (leukocyte adhesion molecule-1, LECAM-1) and increase in CD11b/CD18. Thus, although the above agonists have been characterized primarily as chemoattractants, our findings demonstrate that these agents can exert a wide range of modulatory effects on neutrophil-endothelial adhesive interactions.
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PMID:In vitro inhibitory effect of IL-8 and other chemoattractants on neutrophil-endothelial adhesive interactions. 138 98

Activation of human monocytes with LPS induces coordinate expression of a number of cytokine genes, including IL-1 alpha, IL-1 beta, TNF-alpha, IL-6, and IL-8. The T cell-derived lymphokine, IL-4, inhibits expression of these genes in monocytes, suggesting that it may be an important physiologic regulator of cytokine production. We have previously shown that IL-4 reduces steady state messenger RNA (mRNA) levels for IL-1 beta in human monocytes by decreasing both IL-1 beta transcription and the t1/2 of newly formed IL-1 beta mRNA transcripts. In the present study, we extend these findings to show that IL-4 similarly accelerates the turnover of IL-6 mRNA in LPS-stimulated monocytes. However, this inhibition of cytokine expression and dramatic increase in the decay rate of cytokine mRNA does not extend to all LPS-inducible genes because IL-4 treatment did not inhibit the expression or accelerate the turnover of mRNA for the IL-1 receptor antagonist (IL-1ra) in the same cells. Although IL-1 beta and IL-1Ra are both LPS-inducible genes, they displayed distinct temporal patterns of expression. Peak steady state mRNA levels for IL-1ra lagged significantly behind that of IL-1 beta, suggesting a possible endogenous mechanism for limiting IL-1 biologic activity. Furthermore, although IL-4 suppressed expression of both IL-1 beta and IL-6, it up-regulated synthesis of IL-1ra mRNA and protein. Thus, IL-4 inhibits production of the proinflammatory cytokine, IL-1 beta, while concomitantly enhancing synthesis of the IL-1ra in activated human monocytes.
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PMID:IL-4 reciprocally regulates IL-1 and IL-1 receptor antagonist expression in human monocytes. 138 62

Alveolar macrophages (AM) mediate lung inflammation by producing lipid and peptide molecules that attract neutrophils (PMN) to the lung. Recently we described two porcine proteins called alveolar macrophage-derived chemotactic factors, AMCF-I and -II, that are potent, efficacious, and specific PMN chemoattractants both in vitro and in vivo. We report here the cloning of the full-length cDNAs which code for each protein. Porcine AM were stimulated for 4 h in vitro with Escherichia coli endotoxin (LPS), and a cDNA library was created from poly(A)(+)-selected mRNA. Specific oligonucleotide probes for AMCF-I and AMCF-II were amplified from the porcine AM cDNA library by the polymerase chain reaction using degenerate oligonucleotide primer pairs derived from the N-terminal amino acid sequences of the proteins. These probes were used to isolate 2 full-length cDNAs of 1466 (AMCF-I) and 1515 (AMCF-II) base pairs. Both cDNAs code for proteins with four cysteine residues containing the C-X-C sequence characteristic of the intercrine-alpha family of neutrophil chemoattractants. AMCF-I shares 74% identity with human IL-8 and 84% identity with rabbit IL-8, and likely represents the porcine homologue of IL-8. By contrast, AMCF-II has no obvious human homologue. AMCF-II shares 53% identity with human neutrophil activating peptide 2. Its shared identity with the GRO-related proteins is as high as 61% (rat CINC/GRO), and its shared identity with the 78 amino acid epithelial cell-derived neutrophil activator (ENA-78) is 67%. AMCF-II may represent a new member of the intercrine-alpha family of neutrophil chemoattractants.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Molecular cloning of porcine alveolar macrophage-derived neutrophil chemotactic factors I and II; identification of porcine IL-8 and another intercrine-alpha protein. 142 Jan 65

Blood monocytes are important cellular sources of a vast array of bioactive substances, including regulatory and chemotactic cytokines. The regulation of these cytokines is of critical importance to the expression of acute and chronic inflammatory responses. IL-7, a T and B cell-activating cytokine, has recently been shown to have stimulatory effects on the expression of several monocyte-derived proinflammatory cytokines. We now describe the induction of IL-8 mRNA and extracellular protein from human blood monocytes by IL-7. The up-regulation of IL-8 mRNA by IL-7 was not altered by concomitant treatment with cycloheximide, suggesting that the direct stimulatory effects of IL-7 were not dependent upon de novo protein synthesis. In addition, IL-7 significantly potentiated the production of IL-8 from LPS-, TNF-, and IL-1-treated peripheral blood monocytes. Our findings suggest that IL-7 may play a critical role in the modulation of macrophage-derived cytokine expression and may function in vivo as an important proinflammatory cytokine.
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PMID:IL-7 up-regulates the expression of IL-8 from resting and stimulated human blood monocytes. 151 67


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