Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An extract from the parenchyma of Aloe barbadensis Miller shown to contain long chain polydispersed beta (1,4)-linked mannan polymers with random O-acetyl groups (acemannan, Carrisyn) was found to initiate the phagocyte production of monokines that supported antibody dependent cellular cytotoxicity and stimulated blastogenesis in thymocytes. Acemannan, in both enriched and highly purified forms, was administered intraperitoneally to female CFW mice into which murine sarcoma cells had been subcutaneously implanted. The rapidly growing, highly malignant and invasive sarcoma grew in 100% of implanted control animals, resulting in mortality in 20 to 46 days, dependent on the number of cells implanted. Approximately 40% of animals treated with acemannan at the time of tumor cell implantation (1.5 x 10(6) cells) survived. Tumors in acemannan-treated animals exhibited vascular congestion, edema, polymorphonuclear leukocyte infiltration, and central necrosing foci with hemorrhage and peripheral fibrosis. The data indicate that in vivo treatment of peritoneal macrophages stimulates the macrophage production of monokines, including interleukin-1 and tumor necrosis factor. The data further indicate that sarcomas in animals treated i.p. with acemannan at the time of tumor cell implantation were infiltrated by immune system cells, became necrotic, and regressed. The combined data suggest that acemannan-stimulated synthesis of monokines resulted in the initiation of immune attack, necrosis, and regression of implanted sarcomas in mice.
Mol Biother 1991 Jun
PMID:Decreased mortality of Norman murine sarcoma in mice treated with the immunomodulator, Acemannan. 191 Jun 24

In silicosis, alveolar macrophages (AM) are thought to induce chronic inflammation and fibrosis by release of cytokines. Rats were exposed to aerosols of alpha-quartz and examined 4 to 9 mo later for persistence of silica particles and release of tumor necrosis factor-alpha (TNF-alpha) from macrophages. Silica particles were detected in AM, lung parenchyma, and thoracic lymphoid organs, whereas extrathoracic lymphoid tissues and organs were free of the mineral. When AM were tested functionally, no spontaneous release of TNF-alpha was observed. However, upon in vitro stimulation of AM from silicotic rats with a low concentration of lipopolysaccharide (10 ng/ml), abundant TNF-alpha production was found that was higher and occurred more rapidly than with AM from sham-exposed animals. Peritoneal macrophages, which did not have contact with silica particles, displayed a similarly enhanced TNF-alpha release in response to low doses of lipopolysaccharide. These data demonstrate a state of systemic preactivation ("priming") of macrophages that supports the notion that silicosis is associated with a general immunostimulation.
Am J Respir Cell Mol Biol 1991 Oct
PMID:Systemic macrophage stimulation in rats with silicosis: enhanced release of tumor necrosis factor-alpha from alveolar and peritoneal macrophages. 191 Aug 24

The construction, expression and secretion of two genetically engineered antibody-cytokine hybrid fusion proteins is described. To target tumor necrosis factor (TNF) to tumor cells, recombinant antibody techniques were used to generate F(ab')2-like antibody-TNF fusion proteins. At the gene level, an antitransferrin receptor antibody heavy chain gene was linked to a synthetic gene coding for human TNF. The chimeric heavy chain-TNF genes were introduced into a light chain secreting transfectoma cell line, which was producing the light chain of the same antibody. Cell lines were isolated which secreted antibody-TNF fusion proteins of expected size and composition. Culture supernatant of these cell lines contained TNF cytotoxic activity towards murine L929 cells and human MCF-7 cells, indicating that TNF is still active in the fusion protein constructs. These results illustrate the feasibility of the antibody engineering technology to create and produce chimeric mouse-human immunotoxin-like molecules. Furthermore, they demonstrate the ability of mammalian (myeloma) cells to express and secrete antibody-cytokine hybrid molecules with potential use in anticancer therapy.
Mol Immunol 1991 Sep
PMID:Construction and expression of antibody-tumor necrosis factor fusion proteins. 192 8

We examined the importance of the cytokine tumor necrosis factor-alpha (TNF-alpha) in a mouse model of hypersensitivity pneumonitis (HP). Mice of the C57BL/6 strain were instilled intranasally 3 days/wk for 3 wk with 150 micrograms of the actinomycete Faenia rectivirgula (Micropolyspora faeni) to induce HP as a model of farmer's lung. This experimental model was associated with a progressive inflammation in the lungs of challenged mice, seen histologically as cellular infiltrates of large quantities of macrophages and lymphocytes and some neutrophils. The disease in challenged mice treated with a control rabbit serum was also associated with a substantial release of tumor TNF-alpha (up to 80 U/ml of TNF-alpha in the bronchoalveolar lavage [BAL] at 3 wk after beginning of treatment) and interleukin-1, which peaked at 1 wk (approximately 300 U/ml) and diminished thereafter. A very large increase in BAL cell number (11-fold increase versus saline controls) and an enhanced release potential for TNF-alpha by alveolar macrophages was also seen. Lung fibrosis was also evident in challenged animals, as demonstrated by a 2-fold increase in hydroxyproline levels. Infusion of challenged mice with a rabbit polyclonal antibody against TNF-alpha (2 mg/wk) completely abrogated the disease, as mice so treated had normal lung histology. Anti-TNF-alpha blocked cellular recruitment in the lungs (only a 2-fold increase at week 3); it also completely abolished TNF-alpha secretion in the BAL and drastically reduced interleukin-1 levels in this fluid. Anti-TNF-alpha also abolished lung index increases and lung fibrosis, with both parameters similar to that of saline-instilled mice.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1991 Nov
PMID:Tumor necrosis factor plays an essential role in determining hypersensitivity pneumonitis in a mouse model. 193 Oct 76

The pulmonary fibroblast's (PF) unique location allows it to communicate in a bidirectional fashion between the vascular compartment and alveolar airspace, placing it in a strategic position for the elicitation of inflammatory leukocytes into the lung. In this study, we demonstrate that PF may contribute to pulmonary inflammation through the production of a potent neutrophil chemotactic factor, interleukin (IL)-8. PF-derived IL-8 expression was dependent upon stimulation by either tumor necrosis factor (TNF) or IL-1 but not lipopolysaccharide (LPS). Both TNF and IL-1 stimulation of PF resulted in a time- and dose-dependent expression of steady-state levels of mRNA, antigen, and specific chemotactic activity consistent with IL-8. Because it was apparent that cytokine networking may exist in the lung between alveolar macrophage (AM)-derived cytokines and the production of PF-derived IL-8, we next examined an in vitro model of cellular communication within the lung. We determined that LPS-stimulated AM-conditioned media induced significant levels of PF-derived IL-8 mRNA, which was inhibited by preincubation with specific neutralizing TNF and IL-1 beta antibodies. Furthermore, when AM were directly co-cultured with PF and stimulated with LPS, the kinetic analysis of PF-derived antigenic expression of IL-8 was shifted toward the right. This suggested that PF-derived IL-8 expression in co-culture was first dependent upon activation of the AM by LPS and subsequent elaboration of macrophage inflammatory mediators. These data provide evidence that cytokine networking between AM and PF may be operative in the lung, culminating in the generation of IL-8 and elicitation of inflammatory leukocytes.
Am J Respir Cell Mol Biol 1991 Nov
PMID:Pulmonary fibroblast expression of interleukin-8: a model for alveolar macrophage-derived cytokine networking. 193 Oct 78

The effect of tumor necrosis factor-alpha (TNF) on hyperoxia-induced endothelial injury in vitro was investigated. TNF caused a time- and dose-dependent reduction in the number of viable pulmonary artery endothelial cells. The TNF-mediated endothelial cytotoxicity was more pronounced under hyperoxia (95% O2 and 5% CO2) than under normoxia (95% air and 5% CO2). Pretreatment of endothelial cells with TNF (0.01 micrograms/ml or 240 U/ml) for 18 h at normoxia reduced the intracellular concentration of total glutathione (GSH), whereas the concentration of oxidized GSH was increased. These TNF-treated endothelial cells were more susceptible to hyperoxia- or hydrogen peroxide-mediated cytotoxicity. TNF also induced changes in endothelial morphology and in the distribution and density of actin filaments. Exogenous GSH or L-2-oxothiazolidine-4-carboxylate, which enhanced endothelial GSH concentrations, partially protected endothelial cells against TNF-mediated cytotoxicity, morphologic changes, and actin filament redistribution, especially under the hyperoxic condition. These results suggest an important role of GSH in modulating endothelial response to TNF.
Am J Respir Cell Mol Biol 1991 Dec
PMID:Tumor necrosis factor enhances endothelial cell susceptibility to oxygen toxicity: role of glutathione. 195 83

The human alveolar macrophage (AM) is an important immune effector cell of the lung, as this cell possesses potent antimicrobial activities and has the ability to present antigen. In addition, the Am can secrete a number of regulatory and chemotactic cytokines in response to both endogenous and exogenous stimuli. In this study, we demonstrate that the adherence of AM to plastic or cellular substrates is an important activation event leading to the gene expression of novel chemotactic cytokine interleukin (IL)-8. The culturing of AM on plastic induced the time-dependent accumulation of IL-8 mRNA. In addition, adherence of these cells induced the gene expression of the proinflammatory cytokines tumor necrosis factor-alpha and IL-1 beta. This adherence phenomenon was not specific to plastic, as AM cultured on collagen- or fibronectin-coated plates also expressed IL-8 mRNA upon adherence. The adherence of Am resulted in the induction of de novo IL-8 mRNA synthesis, as this mRNA accumulation was completely abrogated by actinomycin D. Adherence-induced IL-8 mRNA expression was not altered by cycloheximide, suggesting that de novo or ongoing protein synthesis was not required for induction of IL-8 message. Adherence of AM to plastic not only upregulated IL-8 mRNA levels but also induced the production of extracellular IL-8 immunoreactive protein. Both adherent and nonadherent AM treated with lipopolysaccharide generated substantial amounts of IL-8 mRNA. Adherence and lipopolysaccharide, however, acted in a synergistic fashion to dramatically augment the production of extracellular IL-8 from these cells. Our findings would suggest that AM adherence is an important macrophage-activating event that may play a critical role in the modulation of lung inflammatory responses.
Am J Respir Cell Mol Biol 1991 Dec
PMID:Interleukin-8 gene expression from human alveolar macrophages: the role of adherence. 195 85

We isolated clonal sublines of the established mouse marrow stromal cell line, H-1. These clonal sublines underwent differentiation into adipocytes in various degrees. One subline, H-1/A, underwent adipocyte differentiation after confluence, while another subline, H-1/D, did not differentiate. In H-1/A cells, the 4.5- and 2.5-kb major mRNA species of colony-stimulating factor 1 (CSF-1) were expressed before differentiation and were down-regulated at a posttranscriptional level during the differentiation of H-1/A cells. The down-regulation of the CSF-1 gene was not a result of arrested cellular growth, because no down-regulation was detected in the nondifferentiating sister line, H-1/D. This down-regulation appeared to be an early event in differentiation. Cachectin/tumor necrosis factor transiently induced the expression of CSF-1 and inhibited the differentiation of H-1/A cells into adipocytes. This induced expression of CSF-1 was due to an increased rate of transcription.
Mol Cell Biol 1991 Feb
PMID:Colony-stimulating factor 1 expression is down-regulated during the adipocyte differentiation of H-1/A marrow stromal cells and induced by cachectin/tumor necrosis factor. 199 Feb 92

Production and release of lymphotoxin (LT) was studied by metabolic labeling of human B- and T-cell lines with 14C-leucine and 35S-methionine. LT was immunoprecipitated with antiserum to LT and separated by sodium dodecyl sulfate (SDS) polyacrylamide gel electrophoresis (PAGE) followed by fluorography. Two molecular weight forms of LT with different rates of release were found both in cell supernatants and cell extracts. Monensin, a sodium ionophore, inhibited the release of LT. LT still appeared in two molecular weight forms after deglycosylation with N-glycanase. Treatment of cells with swainsonine followed by digestion of released LT with endoglycosidase H (endo H) demonstrated that the oligosaccharides were of the complex type. Subcellular fractionation of cells on Percoll density gradients demonstrated that intracellular LT is located to intermediate density fractions. No LT was found in the high density fractions corresponding to lysosomes. Phorbol 12-myristate 13-acetate induced production of tumor necrosis factor (TNF) in the B-lymphoblastoid cell line RPMI-1788. In conclusion, we have demonstrated the presence of two distinct molecular weight forms of LT, which contain N-linked oligosaccharides of the complex type.
Mol Immunol
PMID:Lymphotoxin produced by human B- and T-cell lines appears in two distinct forms. 201 Nov 32

We have used 125I-labeled fibronectin (FN) as an extracellular substrate for neutrophils (PMN) in order to investigate the mechanism responsible for FN solubilization by PMN and the effects of recombinant cytokines on this process. Pure active alpha 1-antitrypsin (alpha 1AT), when added to PMN before or during, but not after, adherence to FN, inhibited solubilization of the substrate in a dose-dependent manner, but alpha 1AT that had been inactivated by proteolysis or oxidation and alpha 1AT Pittsburgh (alpha 1AT 358Met-Arg) had no significant effect. The solubilization of FN was also inhibited by the PMN elastase inhibitor N-methoxysuccinyl-alanyl-alanyl-prolyl-valine-chloromethylketone but not by the chymotrypsin and cathepsin G inhibitor N-Cbz-glycyl-glycyl-phenylalanine-chloromethylketone, nor by catalase or superoxide dismutase. The products of solubilization of FN by PMN, analyzed by sodium dodecyl sulphate polyacrylamide electrophoresis, were similar to those produced by pure PMN elastase but not cathepsin G. These results suggest that FN solubilization by PMN is caused largely by the pericellular activity of PMN elastase. The solubilization of FN by PMN was increased significantly by adding tumor necrosis factor-alpha, interleukin-1 alpha, or interferon-gamma to the adherent cells but without a significant general release of elastase into the culture supernatants. Granulocyte/macrophage colony-stimulating factor (GM-CSF) had no significant effect. None of the cytokines had any effect when preincubated with the cells in suspension, and non increased FN solubilization by PMN incubated with the optimal (10(-6) mol/liter) or suboptimal dose (10(-8) mol/liter) of the peptide formylmethionylleucylphenylalanine.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1991 Apr
PMID:Extracellular proteolysis of fibronectin by neutrophils: characterization and the effects of recombinant cytokines. 201 99


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