Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.14.14.3 (luciferase)
 38,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Carcinoembryonic Ag-related cellular adhesion molecule 1 (CEACAM1) represents a group of transmembrane protein isoforms that consist of variable numbers of extracellular Ig-like domains together with either a long cytoplasmic (cyt) tail containing two immunoreceptor tyrosine-based inhibitory motifs or a unique short cyt tail. Although CEACAM1 has been reported to be expressed on the surface of T lymphocytes upon activation, its roles in T cell regulation are controversial due to the lack of functional characterization of each individual CEACAM1 isoform. We thus cotransfected Jurkat T cells with CEACAM1 isoform-encoding constructs and an IL-2 promoter-bearing plasmid or a small interference RNA targeting src homology domain 2 containing phosphatase 1. In a luciferase reporter assay and through measurements of cytokine secretion (IL-2, IL-4, and IFN-gamma), CEACAM1 containing either a long or a short cyt tail inhibited or costimulated, respectively, TCR/CD3 complex plus CD28 mediated activation with the inhibitory functions of the long cyt tail dominating. The inhibitory function of CEACAM1, was dependent upon src homology domain 2 containing phosphatase 1 activity, required both tyrosine residues within the immunoreceptor tyrosine-based inhibitory motif domains of the cyt tail and was mediated through the mitogen-activated protein kinase pathway. CEACAM1-mediated inhibition could be functionally reconstituted by incubation of PBMC with either a CEACAM1-specific mAb or CEACAM1-Fc fusion protein in the presence of an allogeneic or mitogenic stimulus, respectively. These studies indicate that the long and short cyt tails of CEACAM1 serve as inhibitory and costimulatory receptors, respectively, in T cell regulation.
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PMID:Carcinoembryonic antigen-related cellular adhesion molecule 1 isoforms alternatively inhibit and costimulate human T cell function. 1500 54

CD1d presents lipid Ags to a specific population of NK T cells, which are involved in the host immune defense, suppression of autoimmunity, and the rejection of tumor cells. The transcriptional control mechanism that determines the regulation and the tissue distribution of CD1d remains largely unknown. After investigating 3.7 kb 5' upstream of the coding region, we found that human gene encoding CD1d molecule (CD1D) has TATA boxless dual promoters with multiple transcription initiation sites. The proximal promoter is located within the region of -106 to +24, and the distal promoter is located within the region of -665 to -202 with the A of the translational start codon defined as +1. The longest 5'-untranslated region derived from 5'-RACE and apparently generated by the distal promoter has 272 bp in length covering the genomic sequence of the proximal promoter. The region covering the proximal promoter gave a much higher luciferase activity in Jurkat cells than in K562 cells, whereas it was in reverse for the region covering the distal promoter, indicating a cell type sp. act. of the two promoters. Transcription factor SP1 plays a crucial role in the function of the proximal promoter. The analysis of the CD1D promoter region indicates that IFN-gamma, NF-IL-6, and T cell factor 1/lymphoid enhancer-binding factor 1 are most likely involved in the regulation of CD1d expression. The illustration of the dual CD1D gene promoters will help to reveal the regulatory factors that control CD1d expression and its tissue distribution for a better understanding of the cross-regulation between CD1d and NK T cells.
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PMID:Human CD1D gene has TATA boxless dual promoters: an SP1-binding element determines the function of the proximal promoter. 1510 Feb 93

The expression of inducible antimicrobial peptides, such as human beta-defensin-2 (HBD-2) by epithelia, comprises a component of innate pulmonary defenses. We hypothesized that HBD-2 induction in airway epithelia is linked to pattern recognition receptors such as the Toll-like receptors (TLRs). We found that primary cultures of well-differentiated human airway epithelia express the mRNA for TLR-4, but little or no MD-2 mRNA, and display little HBD-2 expression in response to treatment with purified endotoxin +/- LPS binding protein (LBP) and soluble CD14. Expression of endogenous MD-2 by transduction of airway epithelial cells with an adenoviral vector encoding MD-2 or extracellular addition of recombinant MD-2 both increased the responses of airway epithelia to endotoxin + LBP and sCD14 by >100-fold, as measured by NF-kappaB-luciferase activity and HBD-2 mRNA expression. MD-2 mRNA could be induced in airway epithelia by exposure of these cells to specific bacterial or host products (e.g., killed Haemophilus influenzae, the P6 outer membrane protein from H. influenzae, or TNF-alpha + IFN-gamma). These findings suggest that MD-2, either coexpressed with TLR-4 or secreted when produced in excess of TLR-4 from neighboring cells, is required for airway epithelia to respond sensitively to endotoxin. The regulation of MD-2 expression in airway epithelia and pulmonary macrophages may serve as a means to modify endotoxin responsiveness in the airway.
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PMID:Endotoxin responsiveness of human airway epithelia is limited by low expression of MD-2. 1512 39

The gene encoding interferon (IFN)-gamma, IFNG, is known as one of the candidate susceptibility genes for type 1 diabetes. In addition, cytokines, including IFN-gamma, play important roles in the pathogenesis of type 1 diabetes. Therefore, we focused on the Th1-specific T-box transcription factor gene (T-bet), which contributes to the induction of the hallmark Th1 cytokine, IFN-gamma. We first screened for polymorphisms in the T-bet gene and detected two microsatellite repeat polymorphisms located in intron 1 and the 3'- flanking region, and two single nucleotide polymorphisms, including a His33Gln substitution within the coding region. By association studies, the Gln-positive phenotype and (CA)14 allele in 3'-flanking region of T-bet were found to be associated with type 1 diabetes in the Japanese population. Furthermore, Gln33 T-bet showed a significantly higher transcriptional activity of the IFNG gene via a dual luciferase reporter assay. Our study suggests the first evidence of an association between type 1 diabetes and polymorphisms in the T-bet gene, and that variation in T-bet transcriptional activity may play a role in the development of type 1 diabetes, possibly through the effect on IFN-gamma production in Th1 cells.
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PMID:Identification of a novel type 1 diabetes susceptibility gene, T-bet. 1524 79

Signaling pathways regulating proliferation, differentiation, and apoptosis are commonly mediated through protein-protein interactions as well as reversible phosphorylation of proteins. To facilitate the study of regulated protein-protein interactions in cells and living animals, we optimized firefly luciferase protein fragment complementation by screening incremental truncation libraries of N- and C-terminal fragments of luciferase. Fused to the rapamycin-binding domain (FRB) of the kinase mammalian target of rapamycin and FK506-binding protein 12 (FKBP), respectively, the optimized FRB-N-terminal luciferase fragment (NLuc)/C-terminal luciferase fragment (CLuc)-FKBP luciferase complementation imaging (LCI) pair reconstituted luciferase activity in cells upon single-site binding of rapamycin in an FK506-competitive manner. LCI was used in three independent applications. In mice bearing implants of cells expressing the FRB-NLuc/CLuc-FKBP LCI pair, dose- and time-dependent luciferase activity allowed target-specific pharmacodynamic analysis of rapamycin-induced protein-protein interactions in vivo. In cells expressing a Cdc25C-NLuc/CLuc-14-3-3epsilon LCI pair, drug-mediated disruption of cell cycle regulated protein-protein interactions was demonstrated with the protein kinase inhibitor UCN-01 in a phosphoserine-dependent manner. When applied to IFN-gamma-dependent activation of Janus kinase/signal transducer and activator of transcription 1 (STAT1), LCI revealed, in the absence of ligand-induced phosphorylation, STAT1 proteins existing in live cells as preformed dimers. Thus, optimized LCI provides a platform for near real-time detection and characterization of regulated and small molecule-induced protein-protein interactions in intact cells and living animals and should enable a wide range of novel applications in drug discovery, chemical genetics, and proteomics research.
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PMID:Kinetics of regulated protein-protein interactions revealed with firefly luciferase complementation imaging in cells and living animals. 1528 40

The activating and inhibitory cytokine signals that act upon epithelial cells in the human lung are critically important for controlling the production of inflammatory mediators from those cells in the context of allergic disease. The cytokines interleukin (IL)-4 and IL-13, derived from T helper (Th)-2 cells and other cell types, are potent inducers of epithelial cell expression of a host of inflammatory molecules, including the chemokines eotaxin-1, -2 and -3. Intracellular signal transduction in response to IL-4/IL-13 occurs largely through activation of signal transducer and activator of transcription 6 (STAT6). Interferon (IFN)-gamma, a Th1-type cytokine, has opposing effects to IL-4/IL-13 in various cell types, including T cells, B-cells, endothelium, and epithelium. In this study, we demonstrate that IL-4-induced STAT6 activation was inhibited profoundly by 24 h pretreatment with IFN-gamma in human primary airway epithelial cell cultures. Using Western blotting, we showed that the levels of both cytoplasmic and nuclear-localized phospho-STAT6 were reduced by IFN-gamma pretreatment, and this effect was dependent on the concentration of IFN-gamma and time of exposure to IFN-gamma. The functional activity of STAT6 was also completely inhibited by IFN-gamma: IL-4-induced luciferase activity from a STAT6-driven reporter construct was suppressed, as was IL-4-induced expression of messenger RNA (mRNA) and protein for eotaxin-3, a STAT6-dependent gene implicated in allergic inflammation. We found that mRNA for suppressor of cytokine signaling (SOCS)-1 and (SOCS)-3, known inhibitors of IL-4 signaling, and IL-13 receptor alpha2, a potential inhibitor of IL-4 signaling, were both strongly induced by IFN-gamma pretreatment. IFN-gamma also increased the rate of decay of IL-4-induced eotaxin-3 mRNA. We conclude that there are multiple mechanisms by which IFN-gamma regulates IL-4- and STAT6-dependent signaling and gene expression in airway epithelial cells. These observations have important implications for the regulation of epithelial cell activation by the balance of Th1/Th2-type cytokines in the airways in allergic disease.
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PMID:Interferon-gamma inhibits STAT6 signal transduction and gene expression in human airway epithelial cells. 1529 69

Using microarray gene expression analysis, we first observed a profound elevation of human beta-defensin-2 (hBD-2) message in IL-17-treated primary human airway epithelial cells. Further comparison of this stimulation with a panel of cytokines (IL-1alpha, 1beta, 2-13, and 15-18; IFN-gamma; GM-CSF; and TNF-alpha) demonstrated that IL-17 was the most potent cytokine to induce hBD-2 message (>75-fold). IL-17-induced stimulation of hBD-2 was time and dose dependent, and this stimulation also occurred at the protein level. Further studies demonstrated that hBD-2 stimulation was attenuated by IL-17R-specific Ab, but not by IL-1R antagonist or the neutralizing anti-IL-6 Ab. This suggests an IL-17R-mediated signaling pathway rather than an IL-17-induced IL-1alphabeta and/or IL-6 autocrine/paracrine loop. hBD-2 stimulation was sensitive to the inhibition of the JAK pathway, and to the inhibitors that affect NF-kappaB translocation and the DNA-binding activity of its p65 NF-kappaB subunit. Transient transfection of airway epithelial cells with an hBD-2 promoter-luciferase reporter gene expression construct demonstrated that IL-17 stimulated promoter-reporter gene activity, suggesting a transcriptional mechanism for hBD-2 induction. These results support an IL-17R-mediated signaling pathway involving JAK and NF-kappaB in the transcriptional stimulation of hBD-2 gene expression in airway epithelium. Because IL-17 has been identified in a number of airway diseases, especially diseases related to microbial infection, these findings provide a new insight into how IL-17 may play an important link between innate and adaptive immunity, thereby combating infection locally within the airway epithelium.
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PMID:IL-17 markedly up-regulates beta-defensin-2 expression in human airway epithelium via JAK and NF-kappaB signaling pathways. 1532 13

Ligands for peroxisome proliferator-activated receptor gamma (PPARgamma), such as 15-deoxy-12,14-PGJ2 (15d-PGJ2), have been proposed as a new class of anti-inflammatory compounds because 15d-PGJ2 was able to inhibit the induction of inflammatory response genes such as inducible NO synthase (iNOS) and TNF (TNF-alpha) in a PPAR-dependent manner in various cell types. In primary astrocytes, the anti-inflammatory effects (inhibition of TNF-alpha, IL-1beta, IL-6, and iNOS gene expression) of 15d-PGJ2 are observed to be independent of PPARgamma. Overexpression (wild-type and dominant-negative forms) of PPARgamma and its antagonist (GW9662) did not alter the 15d-PGJ2-induced inhibition of LPS/IFN-gamma-mediated iNOS and NF-kappaB activation. The 15d-PGJ2 inhibited the inflammatory response by inhibiting IkappaB kinase activity, which leads to the inhibition of degradation of IkappaB and nuclear translocation of p65, thereby regulating the NF-kappaB pathway. Moreover, 15d-PGJ2 also inhibited the LPS/IFN-gamma-induced PI3K-Akt pathway. The 15d-PGJ2 inhibited the recruitment of p300 by NF-kappaB (p65) and down-regulated the p300-mediated induction of iNOS and NF-kappaB luciferase reporter activity. Coexpression of constitutive active Akt and PI3K (p110) reversed the 15d-PGJ2-mediated inhibition of p300-induced iNOS and NF-kappaB luciferase activity. This study demonstrates that 15d-PGJ2 suppresses inflammatory response by inhibiting NF-kappaB signaling at multiple steps as well as by inhibiting the PI3K/Akt pathway independent of PPARgamma in primary astrocytes.
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PMID:The 15-deoxy-delta12,14-prostaglandin J2 inhibits the inflammatory response in primary rat astrocytes via down-regulating multiple steps in phosphatidylinositol 3-kinase-Akt-NF-kappaB-p300 pathway independent of peroxisome proliferator-activated receptor gamma. 1547 65

IFN-gamma (interferon-gamma) has several applications in the treatment of IFN-gamma-related skin disorders. While systemic delivery - the major route used to administer IFN-gamma - results in significant side effects and toxicity, including fever, fatigue, nausea, vomiting and neurotoxicity, transdermal delivery has a very low transduction efficiency. In order to improve the efficiency of transdermal IFN-gamma delivery, we introduced a Pen (penetratin) peptide, a 16-amino-acid-long polypeptide corresponding to the third helix of the DNA-binding domain (homoeodomain) of Antennapedia (a Drosophila transcription factor). The human IFN-gamma gene was then fused with a gene fragment that encodes the Pen of Antennapedia in a bacterial expression vector, producing a genetic in-frame Pen-IFN-gamma. The expressed and purified Pen-IFN-gamma was then found to have a much more efficient transduction profile than native IFN-gamma. In addition, compared with native IFN-gamma, Pen-IFN-gamma exhibited similar activities when added exogenously to a culture medium: (i) induction of IRF-1 gene expression, and (ii) NF-kappaB (nuclear factor kappaB) luciferase reporter activation. These results indicate that the transdermal delivery system using Pen may be an excellent way to replenish IFN-gamma in the various disorders related to this cytokine.
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PMID:Transdermal delivery of interferon-gamma (IFN-gamma) mediated by penetratin, a cell-permeable peptide. 1580 34

The enzymatic action of heme oxygenase (HO) is mediated by the cleavage of heme into carbon monoxide, ferrous iron, and biliverdin/bilirubin. Here, we show that induction of HO-1 expression, an inducible form of HO, down-regulates IFN-gamma-induced MHC class II expression in endothelial cells. Among three catalytic products of HO, bilirubin, but not carbon monoxide or ferrous iron, mediated the suppressive effects of HO through the reduction of mRNA levels of Stat-1-dependent class II transactivator. Expression of HO-1 could suppress the levels of IFN-gamma-induced Stat-1 phosphorylation. This effect could be mimicked by exposing the cells to one of its catalytic products, bilirubin. In addition, HO-1 or bilirubin could modulate the transcript activities of Stat-1-driven gene expression in luciferase reporter assays. These findings suggest an important role of HO-1 in the modulation of immune responses through suppression of MHC-II expression in antigen presenting cells. Our data provide a new line of evidence supporting HO-1-targeted therapy for immune modulation.
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PMID:Bilirubin derived from heme degradation suppresses MHC class II expression in endothelial cells. 1624 3


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