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)

Interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-alpha), and fibronectin are macrophage-derived mediators thought to be important in the pathogenesis of lung injury, inflammation, and fibrosis. In the present studies, we examined the effects of acute exposure of rats to the pulmonary irritant, ozone (O3), on production of these mediators by lung phagocytes. Cells were isolated from lungs 48 h after exposure of rats to air or O3 (2 ppm, 3 h). We found that cells from O3-exposed rats released 2- to 3-fold more IL-1 and TNF-alpha into the culture medium than did cells from air-exposed rats. These effects were time dependent, reaching a maximum at 2 and 24 h for IL-1, and 2 to 4 h for TNF-alpha. We also found that alveolar macrophages from O3-treated rats produced increased amounts of fibronectin, both alone and in response to transforming growth factor-beta, lipopolysaccharide, and interferon-gamma when compared with cells from control rats. Examination of immunohistochemically stained tissue sections indicated increased IL-1, TNF-alpha, and fibronectin in lungs from O3-exposed animals when compared with control animals. IL-1 and TNF-alpha were localized in lung macrophages, whereas fibronectin was associated with blood vessel walls and the lung interstitium. These results demonstrate that lung phagocyte production of these inflammatory mediators is elevated following O3 exposure and suggest that they may play a role in oxidant-induced pulmonary inflammation and injury.
Am J Respir Cell Mol Biol 1994 Sep
PMID:Enhanced production of interleukin-1, tumor necrosis factor-alpha, and fibronectin by rat lung phagocytes following inhalation of a pulmonary irritant. 808 66

Clusterin is an authentic Sertoli cell secretory product initially identified in the ram and rat testis. Subsequent studies have shown that this protein is present in almost all organs and in multiple species. Its mRNA increases in the brain undergoing degeneration as a result of infection, brain injury, and other pathological conditions such as Alzheimer's disease. However, its site(s) of synthesis and modulator(s) in the brain are not known. The objectives of this study were to determine if astrocytes could synthesize and secrete clusterin in vitro and to investigate the effects of various cytokines on the secretion and the mRNA expression of clusterin in the primary cultures of astrocytes. Astrocytes were isolated from cerebral cortices of neonatal rats and enriched to a purity of greater than 95% as judged by immunocytochemical staining using antibody against glial fibrillary acidic protein (GFAP), a specific marker of astrocytes. Using immunoprecipitation techniques, we have demonstrated that astrocytes actively synthesize and secrete clusterin in vitro. Immunocytochemical staining using a monospecific antibody against clusterin showed that this protein is localized in the entire cytoplasm and the processes of astrocytes. Treatment of astrocytes with either interleukin-1 beta, or interleukin-2, induced a significant increase in the production and the mRNA levels of clusterin, whereas other cytokines including interleukin-3, interleukin-6, and interferon-gamma had no apparent effect. The results of this study suggest that clusterin may be a marker to study the immune response in the brain.
Mol Cell Neurosci 1994 Jun
PMID:Regulation of clusterin secretion and mRNA expression in astrocytes by cytokines. 808 21

Normal human peripheral blood mononuclear cells (PBMC) produced IgE when stimulated with IL-4. In the present report it was shown that beta 2-adrenoceptor agonists, salbutamol and fenoterol, potentiated the IL-4-induced IgE production without significantly affecting the expression of the low affinity receptor for IgE at the cell surface of monocytes and B lymphocytes. However, beta 2-adrenoceptor agonists were shown to enhance at day 7 the IL-4-induced release of the soluble form of CD23 (sCD23) by PBMC. This effect was specific since a beta-adrenoceptor antagonist, D,L-propranolol, inhibited the IL-4-induced IgE production by these cells. Alternatively, the beta 2-adrenoceptor agonists inhibited the production by these cells of interferon-gamma (IFN-gamma) but did not affect the production of IL-4 when stimulated with phytohemagglutinin A + a phorbol ester. These data suggest that beta 2-adrenoceptor agonists influence the IL-4-induced IgE production in humans by enhancing the release of sCD23 and inhibiting the production of endogenous IFN-gamma. In addition to the effect on the IL-4-induced IgE production it was shown that beta 2-adrenoceptor agonists potentiated the effect of IL-4 on a human promonocytic cell line, U 937, by enhancing CD23 expression and release and by inducing the differentiation of these cells into monocyte-like cells. Taken together, these data indicate that beta 2-adrenoceptor agonists potentiated the effect of IL-4 and that this functional interaction is different considering the cell-lineage and the stage of differentiation of these cells.
Mol Immunol 1993 Feb
PMID:Functional interaction between beta 2-adrenoceptor agonists and interleukin-4 in the regulation of CD23 expression and release and IgE production in human. 809 28

The correlation between the silver-stained nucleolar organizer region associated proteins (Ag-NORs) and the growth rate suppression (GRS) of ten established breast cancer cell lines which were treated with 4-hydroxy-tamoxifen (OHT) and interferon-gamma (g-IFN), respectively, was investigated by means of automated image analysis. Previous studies have shown a statistically significant relationship between the Ag-NOR quantity and the population doubling time (PDT) of these cell clones. The results of the present study showed a highly significant correlation between the GRS and the Ag-NOR quantity in estrogen receptor (ER) positive tumour cell lines after OHT treatment (P < 0.001) whereas no strict correlation of these parameters could be demonstrated after g-IFN treatment in both ER positive and negative cell lines. Our results suggest a different behaviour of NOR-proteins in breast cancer cell lines if treated either with g-IFN or OHT, probably reflecting the different mechanism of cell suppression mediated by OHT and g-IFN. It is concluded that quantitative assessment of Ag-NORs is not as suitable for the determination of the GRS as it is for the determination of cell duplication rates obtained on untreated tumour cell lines.
Virchows Arch B Cell Pathol Incl Mol Pathol 1993
PMID:Relationship between quantity of silver stained nucleolar organizer region associated proteins (Ag-NORs) and growth rate suppression of breast cancer cell lines after interferon-gamma and 4-hydroxy-tamoxifen treatment. 810 Jun 59

Cytokines and immune cells are likely to be involved in the control of lung metastasis. We have therefore investigated the possibility of inhibiting lung metastases by the means of interferon-gamma (IFN-gamma) aerosolizations in a murine model of lung cancer. A Lewis lung carcinoma (3LL) was inoculated in the thigh of C57BL/6 mice. Randomized groups of 10 mice each were then treated by repeated aerosols of IFN-gamma (4,000 U/mouse) of aerosols of a Hanks' solution as controls. When the animals were killed at 18 days, the number of lung metastatic nodules was significantly reduced (by 50%; P < 0.01) after IFN-gamma aerosols, compared with controls. When the primary tumor was resected at 18 days and aerosols were continued, in the absence of local recurrence, mice treated by IFN-gamma aerosols survived longer than did controls (P < 0.05). In vitro, IFN-gamma exerted no direct antitumoral effect on 3LL cells in culture. Macrophages recovered from mice receiving IFN-gamma aerosols showed a higher antiproliferative effect on 3LL cells in vitro than did controls. Nevertheless, the higher antiproliferative effect of activated macrophages seems insufficient to explain the difference of survival that we observed between IFN-gamma-treated mice and controls.
Am J Respir Cell Mol Biol 1994 Feb
PMID:Antitumoral potential of aerosolized interferon-gamma in mice bearing lung metastases. 811 Apr 75

Local immunoglobulin production has been implicated in the pathogenesis of lung allograft rejection. The role of varying classes of lung accessory cells in stimulating an immunoglobulin (Ig) response in this setting as well as cytokines necessary for Ig synthesis is unknown. The purpose of the current study was to compare the accessory cell capabilities of lung dendritic cells (DC), parenchymal macrophages (PM), and alveolar macrophages (AM) in the generation of a humoral response to alloantigen. Allogeneic AM induced a dose-dependent production of IgG from peripheral blood mononuclear cells. In contrast, allogeneic DC and PM were unable to induce IgG synthesis. The inability of DC to stimulate IgG synthesis was observed despite a potent induction of T-cell proliferation and interferon-gamma (IFN-gamma) production. Additionally, supernatants from DC cultures suppressed AM-induced IgG production, suggesting that a soluble inhibitor of IgG synthesis was produced by DC-stimulated lymphocytes. AM-induced IgG synthesis was predominantly the result of IgG1 and IgG2 production. Experiments with blocking antibodies to either IFN-gamma or interleukin-4 (IL-4) revealed that both IFN-gamma and IL-4 participated in IgG synthesis, while only IFN-gamma was required for IgG2 production. These data demonstrate a discordance between the ability of lung accessory cells to induce T-cell proliferation and IgG synthesis. Furthermore, these findings suggest that local induction of either IL-4 or IFN-gamma is involved in stimulation of an IgG response to lung alloantigen.
Am J Respir Cell Mol Biol 1994 Mar
PMID:Alloantigen-induced immunoglobulin production in human lung: differential effects of accessory cell populations on IgG synthesis. 811 52

In eukaryotes, amino-terminal extensions, signal sequences, mediate the translocation of lysosomal, membrane and secreted proteins into the lumen of the endoplasmic reticulum (ER). Structure/function studies indicate that eukaryotic signal sequences are composed of 3 distinct domains, a positively charged amino-terminal domain, a central hydrophobic domain, and a polar carboxy-terminal domain. In an attempt to better understand protein trafficking in Leishmania we have constructed strains of Leishmania major that secrete an exogenous protein, interferon-gamma (IFN-gamma), under the control of a mammalian signal sequence. In this report we present a mutational analysis of this signal sequence. Deletion of the entire signal sequence or the hydrophobic core region prevents secretion of IFN-gamma and results in cytoplasmic expression of the protein. Mutations in the amino-terminal domain indicate that a net positive charge is not required for efficient secretion of IFN-gamma. Mutations in the carboxy-terminal domain are more complex and display two phenotypes, either they prevent expression of IFN-gamma or they have no effect on protein secretion. These results indicate that the function of the signal sequence in targeting proteins to the ER in Leishmania is similar to that observed in yeasts and higher eukaryotes and suggests that the Leishmania protein secretory apparatus may also be similar.
Mol Biochem Parasitol 1993 Dec
PMID:Mutational analysis of a signal sequence required for protein secretion in Leishmania major. 813 17

Cytokines are thought to cause the depression of cytochrome P-450 (CYP)-associated drug metabolism in humans during inflammation and infection. We have examined the role of five cytokines, i.e., interleukin-1 beta, interleukin-4, interleukin-6, tumor necrosis factor-alpha, and interferon-gamma, on the expression of CYP1A2, CYP2C, CYP2E1, CYP3A, and epoxide hydrolase in primary human hepatocyte cultures. Steady state P-450 and epoxide hydrolase mRNA levels, as well as ethoxyresorufin-O-deethylase and nifedipine oxidation activities, which are mainly supported by CYP1A1/1A2 and CYP3A, respectively, were measured. Interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha were found to be the most potent depressors of P-450 enzymes. After 3 days of treatment, both mRNA levels and enzyme activities were depressed, typically by at least 40%, whatever the cytokine and the enzyme considered. Interferon-gamma also suppressed CYP1A2 and CYP2E1 mRNA levels and ethoxyresorufin-O-deethylase activity but had no effect on CYP3A and epoxide hydrolase mRNAs. In addition, interleukin-4 had the opposite effect, compared with other cytokines, on CYP2E1 mRNA, which was increased up to 5-fold; ethoxyresorufin-O-deethylase and nifedipine oxidation activities were not significantly affected. These results provide the first demonstration that various cytokines act directly on human hepatocytes to affect expression of major P-450 genes and that a wide range of responses can be observed among the enzymes for a given cytokine, suggesting that different regulatory mechanisms may be involved.
Mol Pharmacol 1993 Oct
PMID:Cytokines down-regulate expression of major cytochrome P-450 enzymes in adult human hepatocytes in primary culture. 823 20

Combination of all-trans-retinoic acid (RA) with either interferon-alpha or -gamma resulted in a synergistic amplification of the anti-proliferative effect on cultured breast cancer cells. RA could be replaced by other biologically active retinoids. The synergism was also observed for the induction of 2'-5'-oligoadenylate synthetase, an enzyme which is involved in anti-viral activity of interferons and possibly in growth regulation of tumor cells. Combination of RA with interferon-gamma increased the down-regulation of specific binding sites for [125I]interferon-gamma. On the other hand interferons had no effect on the cytoplasmic binding protein for RA. Comparing all-trans- with 9-cis-RA, the latter was more effective in inhibiting tumor cell growth and in inducing synergism with interferon-gamma. This would indicate that retinoic X receptors are more important in mediating these effects than the RA receptors (RARs). This assumption is also supported by the failure of Ro-415253, a specific RAR-alpha antagonist, to reduce the synergistic interaction of RA with interferon with respect to growth inhibition.
J Steroid Biochem Mol Biol 1993 Dec
PMID:Mechanism of synergistic action of all-trans- or 9-cis-retinoic acid and interferons in breast cancer cells. 827 26

The effects of interferon-gamma (IFN-gamma) were investigated on cytoplasmic motility of alveolar macrophages (AM) from rat lungs in vitro. Cytoplasmic motility was examined by measuring remnant field strength from the cell surface of AM containing Fe3O4 particles, and the relaxation rate (lambda 0; min-1), which is related to cytoplasmic motility, was determined. IFN-gamma caused an increase in lambda 0 in a concentration-dependent fashion with the maximal effect at 1,000 U. Dibutyryl cyclic GMP (db cyclic GMP; 10(-3) M) mimicked IFN-gamma-induced effects, but db cyclic AMP (10(-3) M) decreased lambda 0. IFN-gamma (1,000 U)-induced increases in lambda 0 were concentration-dependently inhibited by NG-monomethyl-L-arginine (L-NMMA) with complete inhibition of a concentration of 10(-4) M and were also completely inhibited by either methylene blue (10(-5) M) or KT 5823 (10(-5) M), a specific inhibitor of protein kinase G. IFN-gamma (1,000 U) caused significant nitrite (NO2-) production from the control values of 0.2 +/- 0.1 to 10.0 +/- 0.2 microM/24 h per 10(6) cells (P < 0.001, n = 10), and this increase in NO2- production by IFN-gamma (1,000 U) was completely inhibited by L-NMMA (10(-4) M). IFN-gamma caused a concentration-dependent increase in a filamentous-actin (F-actin) content with the maximal effect at 1,000 U. db cyclic GMP (10(-3) M) mimicked IFN-gamma induced effects on F-actin formation.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1994 Jan
PMID:Interferon-gamma increases cytoplasmic motility of alveolar macrophages via nitric oxide-dependent signaling pathways. 829 82


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