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)

Cytokines are hormones that carry information from cell to cell. This information is read from their surface upon binding to transmembrane receptors and by the subsequent initiation of receptor oligomerization. An influence on this process through mutagenesis on the hormone surface is highly desirable for medical reasons. However, an understanding of hormone-receptor interactions requires insight into the structural changes introduced by the mutations. In this line structural studies on human IL-4 and the medically important IL-4 antagonists Y124D and Y124G are presented. The site around Y124 is an important epitope responsible for the ability of IL-4 to cause a signal in the target cells. It is shown that the local main-chain structure around residue 124 in the variants remains unchanged. A strategy is presented here which allows the study of these types of proteins and their variants by NMR which does not require carbon labelled samples.
J Mol Biol 1994 Apr 08
PMID:Aspects of receptor binding and signalling of interleukin-4 investigated by site-directed mutagenesis and NMR spectroscopy. 815 3

Asthma is characterized by the presence of an inflammatory cell infiltrate in the bronchial mucosa consisting of activated mast cells, eosinophils, and T cells. Several cytokines are considered to play a pivotal role in this response, particularly interleukin (IL)-4, IL-5, IL-6, and tumor necrosis factor-alpha (TNF-alpha). In this study, we have used immunohistochemistry applied to thin glycol methacrylate sections of bronchial mucosal biopsies to define the cellular provenance of these cytokines in normal and asthmatic airways. Both the asthmatic and normal mucosa contained numerous cells staining positively for all four cytokines, with the majority identified as mast cells by their tryptase content. Eosinophils also accounted for some IL-5 immunostaining in the asthmatic biopsies. By using two monoclonal antibodies directed to different epitopes of IL-4, we provide tentative evidence for enhanced IL-4 secretion in asthma. Similarly, a sevenfold increase in the number of mast cells staining for TNF-alpha in the asthmatic biopsies suggests that this cytokine is also up-regulated in this disease. These findings clearly identify human mast cells as a source of IL-4, IL-5, IL-6, and TNF-alpha and add to the view that, along with T cells, mast cells may play an important role in initiating and maintaining the inflammatory response in asthma.
Am J Respir Cell Mol Biol 1994 May
PMID:Interleukin-4, -5, and -6 and tumor necrosis factor-alpha in normal and asthmatic airways: evidence for the human mast cell as a source of these cytokines. 817 9

We have isolated and characterized a new MHC class II transcription mutant cell line, called UV. This cell line was derived from the mouse B lymphoma A20 by UV light-induced mutagenesis and immunoselection for the loss of surface MHC class II molecules. It expresses only 5% of the level of MHC class II molecules on A20 and this is associated with a similar reduction of class II specific mRNA. This defect cannot be restored by the MHC class II transcription inducers, IL-4 and IFN gamma, confirming that the mutation acts at the transcription level. The mutation also affects MHC class I expression, but the transcription of class I molecules is not affected. In contrast, the expression of other markers, such as the invariant chain and the surface immunoglobulins G and M, is not modified. Such a variant should prove useful for the study of the transcription factors involved in the regulation of MHC class II expression.
Mol Immunol 1993 Nov
PMID:Isolation and characterization of a new murine MHC class II transcription mutant cell line. 823 29

Egr-1 is an immediate early gene that is rapidly upregulated in response to mitogenic signals induced by antigen receptor crosslinking on murine B lymphocytes. It has been shown that levels of Egr-1 expression are closely correlated with B cell proliferation in several models of B cell activation and tolerance. We compared the expression of Egr-1 during B cell stimulation with Fab'2 and IgG anti-immunoglobulin (anti-Ig), since it is known that Fab'2 anti-Ig is mitogenic while IgG anti-Ig is not, owing to a dominant inhibitory effect of crosslinking the B cell Fc gamma RII to membrane Ig. While mitogenic doses of Fab'2 anti-Ig induce large and rapid increases in Egr-1 expression, IgG anti-Ig results in smaller increases in Egr-1 mRNA, comparable to that seen with submitogenic concentrations of Fab'2 anti-Ig. However, the correlation between Egr-1 expression and B cell proliferation breaks down when IL-4 is added as a co-mitogen to induce B cell proliferation with IgG anti-Ig or submitogenic concentrations of Fab'2 anti-Ig. No corresponding increases in Egr-1 mRNA levels are observed when IL-4 is added. Therefore, IL-4 overcomes Fc receptor-mediated inhibition of B cell proliferation without affecting inhibition of Egr-1 mRNA induction, as demonstrated earlier for c-myc mRNA in this system.
Mol Immunol 1993 Nov
PMID:Effects of IL-4 and Fc gamma receptor II engagement on Egr-1 expression during stimulation of B lymphocytes by membrane immunoglobulin crosslinking. 823 40

Expression of the granulocyte-macrophage colony-stimulating factor (GM-CSF) gene in T cells is activated by the combination of phorbol ester (phorbol myristate acetate) and calcium ionophore (A23187), which mimic antigen stimulation through the T-cell receptor. We have previously shown that a fragment containing bp -95 to +27 of the mouse GM-CSF promoter can confer inducibility to reporter genes in the human Jurkat T-cell line. Here we use an in vitro transcription system to demonstrate that a cis-acting element (positions -54 to -40), referred to as CLE0, is a target for the induction signals. We observed induction with templates containing intact CLE0 but not with templates with deleted or mutated CLE0. We also observed that two distinct signals were required for the stimulation through CLE0, since only extracts from cells treated with both phorbol myristate acetate and A23187 supported optimal induction. Stimulation probably was mediated by CLE0-binding proteins because depletion of these proteins specifically reduced GM-CSF transcription. One of the binding factors possessed biochemical and immunological features identical to those of the transcription factor AP1. Another factor resembled the T-cell-specific factor NFAT. The characteristics of these two factors are consistent with their involvement in GM-CSF induction. The presence of CLE0-like elements in the promoters of interleukin-3 (IL-3), IL-4, IL-5, GM-CSF, and NFAT sites in the IL-2 promoter suggests that the factors we detected, or related factors that recognize these sites, may account for the coordinate induction of these genes during T-cell activation.
Mol Cell Biol 1993 Dec
PMID:The granulocyte-macrophage colony-stimulating factor promoter cis-acting element CLE0 mediates induction signals in T cells and is recognized by factors related to AP1 and NFAT. 824 60

Interleukin-5 (IL-5) and IL-6 have both been reported to act as B-cell differentiation factors by stimulating activated B cells to secrete antibody. However, it has not been possible to directly compare the effects of these two lymphokines because of the lack of a suitable B-cell line capable of responding to both. We have identified a clonal, inducible B-cell lymphoma, CH12, that has this property. Both IL-5 and IL-6 can independently stimulate increases in steady-state levels of immunoglobulin and J-chain mRNA and proteins, and they both induce the differentiation of CH12 into high-rate antibody-secreting cells. Nevertheless, there are significant differences in the activities of these two lymphokines. First, while IL-6 acts only as a differentiation factor, IL-5 also augments the proliferation of CH12 cells. Second, the differentiation stimulated by IL-5 but not by IL-6 is partially inhibited by IL-4. Inhibition of IL-5-induced differentiation was not at the level of IL-5 receptor expression, since IL-4 did not inhibit IL-5-induced proliferation. Third, IL-5 but not IL-6 stimulated increased mouse mammary tumor proviral gene expression in CH12 cells. These results demonstrate that while both IL-5 and IL-6 may act as differentiation factors for B cells, they induce differentiation by using at least partially distinct molecular pathways. Our results also establish that B cells characteristic of a single stage of development can independently respond to IL-4, IL-5, and IL-6.
Mol Cell Biol 1993 Jul
PMID:Interleukin-5 (IL-5) and IL-6 define two molecularly distinct pathways of B-cell differentiation. 832 Dec

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

The gene for the mouse low affinity receptor for IgE (Fc epsilon RII, also known as CD23) was mapped on Chromosome (Chr) 8 proximal to Plat. This gene, symbolized Fcer2 (formerly Fce2) resides in a region of Chr 8 with linkage homology with human chromosomes 8 and 19. The mouse Fc epsilon RII was examined for the presence of alternate N-terminal forms such as seen in humans. An antisense RNA probe was prepared from the 5' end of the cDNA through the first 660 bp of the cDNA and was used to analyze message from Fc epsilon RII+ B cells and B cell hybridomas both before and after treatment with interleukin 4 (IL-4). Using RNase protection analysis, a major 640 bp band corresponding to the full length probe was seen, even after activation of the cells with LPS in the presence of IL-4, which is known to give high expression levels of the Fc epsilon RII. This result suggests that the mouse does not produce significant levels of an alternate IL-4 inducible Fc epsilon RII, as seen in man, and this may explain the more restricted cell lineage expression of the Fc epsilon RII in the mouse.
Mol Immunol 1993 Jan
PMID:Chromosomal location and isoform analysis of mouse Fc epsilon RII/CD23. 841 72

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


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