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)

Studies with animal models have indicated that neutralizing antibodies against human interferon-gamma (HuIFN-gamma) may be used to treat a number of diseases in man. A major handicap for the implementation of this form of therapy is the immunogenicity of antibodies of non-human origin. Antibody fragments that do not contain parts of the most immunogenic regions may help to circumvent this problem. Therefore, we have constructed several antibody fragments [VH (variable fragment of the heavy chain), Fv (variable fragment) and scFv (single-chain Fv)] derived from a murine hybridoma (D9D10) which produces a neutralizing antibody against HuIFN-gamma. cDNAs encoding the variable domains of the L and H chains of D9D10 were cloned by PCR-based techniques in a suitable E. coli expression system. Bacterial clones are described that produce either VH, Fv or scFv. The Ig fragments were secreted into the periplasm and leaked into the culture supernatant. By SDS-PAGE and immunoblot analysis, the fragments were shown to be of the expected size (15, 14 and 30 kDa for VH, Fv and scFv, respectively). Functionality of the recombinant Ig fragments was tested by an ELISA for HuIFN-gamma binding and by a neutralization assay for the antiviral activity of HuIFN-gamma. Fv as well as scFv, but not VH, were found to bind to HuIFN-gamma and to neutralize its antiviral activity. Since it is found that scFv proteins are more stable at physiological temperatures than the Fv, it may have potential usefulness for the treatment of diseases in which overproduction of IFN-gamma plays a crucial role.
Mol Immunol 1993 Jun
PMID:Bacterial expression of a single-chain antibody fragment (SCFV) that neutralizes the biological activity of human interferon-gamma. 832 Dec 46

B lymphocytes are crucial participants in pulmonary immune defense. However, excess local antibody production is associated with accelerated lung destruction in several types of lung disease. The purpose of the current study was to study the potential role of alveolar macrophages (AM) in the local regulation of immunoglobulin (Ig) production in the lung in response to a direct B cell mitogen, Staphylococcus aureus Cowan strain (SAC). AM, when added to peripheral blood mononuclear cells, caused a dose-dependent inhibition of IgG and IgM, while not affecting IgA production in response to SAC. The mechanism of the AM-induced inhibition included both membrane-bound and soluble signals. The inhibition was not abrogated by indocin and catalase, or reversed by blocking antibodies to transforming growth factor-beta or interferon-gamma. Mononuclear cells isolated from human lung parenchyma displayed a reduced response to SAC compared with blood cells. However, depletion of macrophages from the parenchymal cells was associated with a restoration of IgG production in response to SAC. The results demonstrate that AM inhibit B cell responses to direct B cell mitogen and suggest that the effect of AM is selective for IgM and IgG.
Am J Respir Cell Mol Biol 1993 Aug
PMID:Human alveolar macrophages inhibit immunoglobulin production in response to direct B cell mitogen. 833 83

Class II MHC protein expression in macrophages (M phi) is reduced during tumor growth. Because regulation of class II MHC proteins occurs during transcription, tumor growth may suppress class II MHC protein expression by suppressing mRNA. The decrease in class II mRNA may result from (i) a decrease in M phi responsiveness to an inducing agent, such as interferon-gamma (IFN-gamma), or (ii) an increase in M phi sensitivity to suppressing agents, such as prostaglandin E2 (PGE2). To determine how tumors induce suppression of class II mRNA, M phi were cultured in the presence of IFN-gamma with or without other factors, and Northern blot analyses were performed. Unstimulated normal host (NH) or tumor-bearing host (TBH) M phi do not express detectable class II mRNA. The addition of IFN-gamma induces class II mRNA expression in NH and TBH M phi, but class II mRNA expression is significantly lower in TBH M phi. Kinetic studies suggested that NH M phi class II mRNA is induced faster and in greater amounts than TBH M phi class II mRNA. There is a decrease in M phi class II mRNA stability during tumor growth that may account for the decreased induction by IFN-gamma. Lipopolysaccharide (LPS) suppresses class II mRNA induction in both NH and TBH IFN-gamma-treated M phi, but TBH M phi are more sensitive to its suppression. PGE2 and tumor-necrosis factor-alpha (TNF-alpha), two factors produced by LPS-stimulated M phi, were tested for their ability to modulate class II mRNA expression in NH and TBH IFN-gamma-treated M phi. PGE2 suppressed class II mRNA expression in both NH and TBH M phi. The addition of TNF-alpha to IFN-gamma-treated M phi suppressed class II mRNA in NH M phi but, surprisingly, had an additive effect on IFN-gamma-induced class II mRNA expression. TNF-alpha did not induce class II mRNA expression in TBH M phi in the absence of IFN-gamma. The cause of the reduced class II mRNA expression during tumor growth is a decreased response to IFN-gamma and an increased sensitivity to PGE2. This change may cause the observed suppression mediated by TBH M phi.
Mol Immunol 1993 Jul
PMID:Tumor-induced modulation of macrophage class II MHC molecule mRNA expression. 834 Dec 83

An endothelial cell line (M40) resistant to growth inhibition by transforming growth factor-beta type 1 (TGF beta 1) was isolated by chemical mutagenesis and growth in the presence of TGF beta 1. Like normal endothelial cells, this mutant is characterized by high expression of type II TGF beta receptor and low expression of type I TGF beta receptor. However, the mutant cells display a type II TGF beta receptor of reduced molecular weight as a result of a general defect in N-glycosylation of proteins. The alteration does not impair TGF beta 1 binding to cell surface receptors or the ability of TGF beta 1 to induce fibronectin or plasminogen activator inhibitor-type I production. M40 cells were also resistant to growth inhibition by tumor necrosis factor alpha (TNF alpha) and interleukin-1 alpha (IL-1 alpha) but were inhibited by interferon-gamma (IFN gamma) and heparin. These results imply that TGF beta 1, TNF alpha, and IL-1 alpha act through signal transducing pathways that are separate from pathways for IFN gamma and heparin. Basic fibroblast growth factor was still mitogenic for M40, further suggesting that TGF beta 1, TNF alpha, and IL-1 alpha act by direct inhibition of cell growth rather than by interfering with growth stimulatory pathways.
Mol Biol Cell 1993 Feb
PMID:A glycosylation-deficient endothelial cell mutant with modified responses to transforming growth factor-beta and other growth inhibitory cytokines: evidence for multiple growth inhibitory signal transduction pathways. 838 75

Insulin-like growth factor-II (IGF-II) gene expression is induced by adrenocorticotropic hormone (ACTH) in human fetal adrenals (HFA), which suggests an important role for IGF-II in HFA growth and differentiation. Many cytokines have different regulatory actions in the endocrine glands. In the present study we have investigated the effects of two cytokines, tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma), on the regulation of IGF-II gene expression in cultured HFA cells. Both TNF-alpha and IFN-gamma inhibited basal and ACTH-induced accumulation of IGF-II mRNA dose-dependently. Cell viability was not altered by treatment with TNF-alpha or IFN-gamma. In addition, the combination of TNF-alpha and IFN-gamma decreased ACTH-induced IGF-II mRNAs more potently than each cytokine alone. Our results suggest that TNF-alpha and IFN-gamma may be involved in the regulation of HFA growth and differentiation via local IGF-II production.
Mol Cell Endocrinol 1993 Feb
PMID:Tumor necrosis factor-alpha and interferon-gamma inhibit insulin-like growth factor II gene expression in human fetal adrenal cell cultures. 838 14

Human gamma delta T cell clones having V gamma 9JP and V delta 2DJ1 T cell receptor (TCR) gene rearrangements were isolated form an individual donor and tested for non-MHC restricted cytotoxicity against the B lymphoblastoid cell line, BSM. Most clones were highly cytotoxic but 3/9 clones had very low activity, comparable to that of CD4+ alpha beta T cell clones. Although there was a tendency for clones with low cytotoxic function to produce high levels of interferon-gamma and tumor necrosis factor-alpha, this correlation was not complete. TCR gamma and delta junctional sequences were obtained and were found to be different for all clones. There were no consistent structural differences between gamma delta TCRs of cytotoxic and non-cytotoxic clones, but gamma or delta junctional regions of all three non-cytotoxic clones had unusual features. One clone had a particularly short gamma chain junctional sequence, one had a short delta chain junctional sequence and the third clone was the only one of the panel which failed to utilise the D delta 3 segment. If the gamma delta TCR is involved in target cell recognition in this model of non-MHC restricted killing, such variations in receptor structure may be sufficient to inhibit recognition and thereby reduce the cytotoxic capacity of a minority of V gamma 9+/V delta 2+ clones. Also, a panel of gamma delta T cell clones expressing V gamma 8/V delta 3 isolated from a different donor, were all highly cytotoxic against BSM, indicating that these target cells can be recognised by effector cells expressing a TCR other than the V gamma 9/V delta 2 receptor. The possible influence of other cell surface molecules on non-MHC restricted cytotoxic function is discussed.
Mol Immunol 1993 May
PMID:T cell receptor junctional regions of V gamma 9+/V delta 2+ T cell clones in relation to non-MHC restricted cytotoxic activity. 838 36

Although studies of nitrogen dioxide (NO2) inhalation, in both animals and humans, have demonstrated that this agent can cause epithelial cell damage and inflammation of the airway epithelium, the mechanisms underlying these effects are not well understood. We have cultured human bronchial epithelial cells, as explant cultures from surgical tissue, and studied these firstly from their ability to constitutively synthesize specific proinflammatory cytokines and then investigated the effect of exposure to NO2 on the generation of these cytokines. Constitutive synthesis of cytokines was evaluated by analysis of both the expression of the mRNA for interleukin (IL)-1 beta, IL-4, IL-8, granulocyte/macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma), by the polymerase chain reaction (PCR), and by immunocytochemical staining for the presence of cell-associated IL-1 beta, IL-8, GM-CSF, TNF-alpha, and IFN-gamma, using specific monoclonal and polyclonal antibodies directed towards these cytokines. Release of IL-4, IL-8, GM-CSF, TNF-alpha, and IFN-gamma following exposure to 5% CO2 in air or 400 ppb and 800 ppb NO2 for 6 h was investigated by enzyme-linked immunosorbent assay. PCR demonstrated that the human bronchial epithelial cells expressed the mRNA for IL-1 beta, IL-8, GM-CSF, and TNF-alpha but not for IL-4 and IFN-gamma. Immunocytochemical staining confirmed the presence of endogenous IL-1 beta, IL-8, GM-CSF, and TNF-alpha.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1993 Sep
PMID:Effect of nitrogen dioxide on synthesis of inflammatory cytokines expressed by human bronchial epithelial cells in vitro. 839 64

Immunohistology and in situ hybridization were used to evaluate the presence, activation status, and cytokine mRNA profile of cells in the bronchial mucosa during human allergen-induced asthma. Fifteen atopic asthmatic subjects underwent inhalation challenge with allergen and with allergen diluent, performed in random order separated by an interval of at least 3 wk. Bronchial biopsies were obtained 24 h after challenge. Immunostaining revealed increases in the numbers of secreting eosinophils (EG2+; P < 0.05) and in interleukin-2 receptor (IL-2R)-positive cells (CD25+; P < 0.01) after allergen compared with diluent challenge. No differences were observed in the numbers of total leukocytes (CD45+), T lymphocytes (CD3+, CD4+, and CD8+), elastase-positive neutrophils, macrophages (CD68+), or mast cell subtypes (MCT+ or MCTC+). In situ hybridization revealed significant increases in the numbers of cells expressing mRNA for IL-5 (P < 0.02) and granulocyte/macrophage colony-stimulating factor (P < 0.01) after allergen compared with diluent challenge. A significant inverse relationship was observed between the number of cells expressing mRNA for IL-4 and for interferon-gamma (r = -0.75, P < 0.02). The results support the view that cytokines possibly from activated T lymphocytes may contribute to local eosinophil accumulation during allergen-induced asthma.
Am J Respir Cell Mol Biol 1993 Jan
PMID:Increases in activated T lymphocytes, eosinophils, and cytokine mRNA expression for interleukin-5 and granulocyte/macrophage colony-stimulating factor in bronchial biopsies after allergen inhalation challenge in atopic asthmatics. 841 55

It has been reported that the interleukin 4 (IL-4) specific induction of cell surface CD23 (Fc epsilon RII) is down-regulated by interferon-gamma (IFN-gamma) in monocytes and B cells. However, the molecular level at which the inhibition occurs seems to vary depending on the cell types. In normal human B cells, IFN-gamma inhibits the IL-4 induced de novo synthesis of CD23 at the level of gene expression. Analysis of inhibition kinetics suggested a rapid signal transmission by IFN-gamma. Yet the inhibitory action of IFN-gamma on CD23 mRNA accumulation appeared as a secondary response requiring a new protein synthesis. Through nuclear run-on transcription and mRNA stability studies, we further demonstrate that the IL-4 induced CD23 gene expression is down-regulated by IFN-gamma mainly at post-transcriptional levels by decreasing mRNA stability.
Mol Immunol 1993 Feb
PMID:Mechanism of interferon-gamma down-regulation of the interleukin 4-induced CD23/Fc epsilon RII expression in human B cells: post-transcriptional modulation by interferon-gamma. 843 8

Transport of secretory IgA into external fluids is mediated by the polymeric immunoglobulin receptor (pIgR) on the surface of mucosal epithelial cells. We studied the mechanism by which interferon-gamma (IFN-gamma) induces pIgR expression in HT-29.74 cells, a subclone of the HT-29 cell line selected for high concns of pIgR. Here we report the isolation of genomic DNA and cDNA clones encoding human pIgR and development of a sensitive ribonuclease protection assay for pIgR mRNA. This assay was used to determine if induction of pIgR by IFN-gamma is mediated by accumulation of pIgR mRNA. After an initial lag of 12 hr, pIgR mRNA increased seven-fold in response to IFN-gamma, reaching a plateau at 24 hr. Concentrations of pIgR protein also increased seven-fold, but the increase was delayed until 48 hr following stimulation with IFN-gamma. Cycloheximide treatment abolished the IFN-gamma induced increase in pIgR mRNA, indicating that induction of pIgR mRNA by IFN-gamma requires de novo protein synthesis. These results suggest that induction of pIgR expression by IFN-gamma involves an increase in steady-state concns of pIgR mRNA via a protein synthesis dependent mechanism.
Mol Immunol 1993 Mar
PMID:Interferon-gamma induces polymeric immunoglobulin receptor mRNA in human intestinal epithelial cells by a protein synthesis dependent mechanism. 845 39


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