Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.48 (transcriptase)
9,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human intercellular adhesion molecule-1 (ICAM-1), a specific ligand for the lymphocyte function-associated Ag-1 (LFA-1), plays an important role in leukocyte-endothelial cell interactions. It is induced by proinflammatory cytokines such as IL-1, TNF-alpha, or IFN-gamma. However, little is known concerning the intracellular regulatory mechanisms which trigger ICAM-1 up-regulation. In order to study potential regulatory elements involved in ICAM-1 induction we have cloned the human ICAM-1 gene and 5 kb of its 5'-regulatory region. The sequence of the cDNA was found to be distributed over seven exons separated by six introns, whereby each of the five extracellular Ig-like domains of ICAM-1 is encoded by its own exon. The upstream sequence harbors a number of sequence motifs implicated in the regulation and expression of eukaryotic genes, including binding sites for the transcription factors SP-1, AP-1, and NF-kB. Primer extension and S1 nuclease analysis revealed two transcription initiation sites 319 bp and 41 bp upstream of the translation start site. Consensus TATA boxes were found at the expected positions about 25 bp upstream of both start sites. Reverse transcriptase polymerase chain reaction showed differential use of the two TATA boxes in A549 and HS913T cells. Both RNA seem to code for the same for of ICAM-1 protein. For regulation studies a 1.3-kb EcoRI/SalI fragment of the 5'-flanking region was used to promote transcription of a linked luciferase reporter gene in transient-transfection assays in A549 and HS913T cells. Treatment of A549 cells with IL-1 or TNF-alpha resulted in a two- or fourfold increase in luciferase activity. Furthermore, a sixfold induction could be achieved after treatment with the phorbol ester PMA. In contrast, agents that increase intracellular cAMP levels did not induce luciferase activity. Northern blot analysis was used to investigate the kinetics of ICAM-1 mRNA synthesis upon induction with TNF-alpha and PMA. These data suggest that the up-regulation of ICAM-1 by cytokines occurs at least partly at the transcriptional level. Deletion analysis of the 1.3-kb fragment of the 5'-flanking region revealed sequences responsible for promotion and inhibition of transcription. In particular, two functionally distinct regions have been characterized: a short fragment containing an NF-kB binding site has been shown to function as an activator, followed immediately downstream by a sequence acting as a silencer element. Therefore, ICAM-1 gene expression seems to be modulated by multiple cis-acting elements.
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PMID:Cloning of the human gene for intercellular adhesion molecule 1 and analysis of its 5'-regulatory region. Induction by cytokines and phorbol ester. 168 Sep 19

Simian immunodeficiency viruses (SIV) are a family of primate lentiviruses similar to human immunodeficiency viruses (HIV) in their genetic sequence and pathogenesis. However, host-derived cofactors which may determine the extent of viral replication are not clearly defined for SIV or HIV infections. A HuT-78 cell line chronically infected with SIV/mac strain 251, was biologically cloned and characterized for the ability to produce infectious viral particles, viral structural protein profile, cellular antigen surface phenotype and tested to determine the effects of recombinant cytokines on SIV replication. Reverse transcriptase (RT) assay was used to measure the replication of SIV/mac in response to various concentrations of recombinant cytokines (1-1000 units/ml). We report that tumor necrosis factor-alpha (rTNF-alpha), gamma-interferon (rIFN-gamma), interleukin 2 (rIL-2), and granulocyte-macrophage colony stimulating factor (rGM-CSF) induced approximately a 2 to 3 fold increase in virus RT activity compared with untreated SIV-infected HuT-78 cells. In contrast, viral replication was not enhanced or minimally enhanced by interleukin 1 (rIL-1), interleukin 3 (rIL-3), or interleukin 4 (rIL-4) at similar dosages. Furthermore, SIV replication in response to rTNF-alpha and rIFN-gamma occurred in a dose dependent fashion. These data suggest that SIV-infected T-lymphocyte lines are responsive to particular cytokines resulting in increased virus production.
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PMID:Cytokine enhancement of simian immunodeficiency virus (SIV/mac) from a chronically infected cloned T-cell line (HuT-78). 172 91

The outer surface lipoproteins of Borrelia burgdorferi, OspA and OspB, stimulate the production of nitric oxide (NO) by murine bone marrow-derived macrophages from BALB/c, C3H/HeN, and C3H/HeJ mice. Gamma interferon (IFN-gamma) caused a three- to fivefold enhancement of this production of NO, and the L-arginine analog N-guanidino-monomethyl L-arginine inhibited it. Activation of transcription of the inducible NO synthase gene in stimulated macrophages was demonstrated by reverse transcriptase rapid PCR. Although IFN-gamma increased the amount of NO produced in macrophage cultures, it did not cause transcription of the inducible NO synthase gene greater than that seen with the Borrelia proteins. OspA and OspB also induced the production of high levels (40 to 150 ng/ml) of IFN-gamma in cultures of macrophages incubated with interleukin-2 (IL-2)-elicited cells from normal (T and NK cells) and scid (NK cells) mice but not in macrophages or IL-2-elicited cells cultured individually. This suggests that OspA stimulated macrophage production of cytokines, which, in turn, stimulated the production of IFN-gamma by NK and T cells. Reverse transcriptase rapid PCR demonstrated that OspA and sonicated B. burgdorferi stimulated production of several inflammatory cytokines in macrophage cultures, including IL-1, IL-6, IL-12, IFN-beta, and tumor necrosis factor alpha. As tumor necrosis factor alpha, IFN-beta, and IL-12 are potent activators of IFN-gamma production by T and NK cells, their presence in these cocultures could be responsible for the IFN-gamma production. Lymphocytes from infected C3H mice also produced IFN-gamma when stimulated with B. burgdorferi; thus, immune cells may also modulate NO responses. The generation of NO during infection with B. burgdorferi may be important, as NO has potent antimicrobial properties. NO can also be involved in pathological inflammatory processes in which its generation is detrimental to the host. Thus, the colocalization of B. burgdorferi lipoproteins, NO-producing cells, and regulatory cytokines may determine the outcome of infection.
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PMID:Outer surface lipoproteins of Borrelia burgdorferi stimulate nitric oxide production by the cytokine-inducible pathway. 752 Apr 17

Reverse transcriptase-polymerase chain reaction amplification (RT-PCR) and Southern blot analysis were used to evaluate ligand and receptor expression of interleukin 1 alpha (IL-1 alpha), interleukin 3 (IL-3), interleukin 6 (IL-6) and stem cell factor (SCF) in peripheral blood lymphocytes and monocytes and in several acute leukemia blast cell populations. Resting peripheral lymphocytes and monocytes expressed both ligand and receptor of the four cytokines at considerable levels. The leukemic blast cells of the M1-M4 phenotypes are characterized by almost complete lack of expression of IL-1 alpha, IL-3 and IL-6 and the constant and usually high expression of SCF. On the other hand, these myeloid blast cells express generally high levels of the four cytokine receptors. The data suggest that the regulation of the expression of IL-1 alpha, IL-3 and IL-6, at least in our limited number of leukemic cell populations studied, is independent of that of SCF. The results indicate that, at least in most of the leukemic myeloid blasts cells, the expression of SCF and its receptor, the c-kit oncogene, may permit an autocrine regulation of cell cycling.
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PMID:Expression of interleukins 1, 3, 6, stem cell factor and their receptors in acute leukemia blast cells and in normal peripheral lymphocytes and monocytes. 768 16

Interleukin-1 receptor antagonist (IL-1ra) is an important modulator of IL-1 activity in a variety of tissues. IL-1ra is differentially produced by different cell types as a 22-26-kD secreted peptide (sIL-1ra) and/or a smaller 16- or 18-kD intracellular peptide (icIL-1ra). This study was undertaken to evaluate the production of IL-1ra in the human cornea. IL-1ra mRNA can be detected in early passage human corneal epithelial cells and corneal stromal fibroblasts and is significantly enhanced by IL-1. Corneal endothelial cells do not express IL-1ra mRNA. Immunohistochemical studies of cultured corneal cells and whole human cornea demonstrate IL-1ra protein production by both the epithelial and stromal cells but not the endothelial cells. Reverse transcriptase polymerase chain reaction, ELISA, and immunoprecipitation studies indicate that corneal epithelial cells are capable of producing both icIL-1ra and sIL-1ra forms of IL-1ra whereas the corneal stromal cells produce only icIL-1ra. In addition to the larger 18-kD icIL-1ra, both corneal epithelial and stromal cells are also capable of producing a smaller recently described 16-kD icIL-1ra. Thus, the differential production of IL-1ra in the human cornea is unique; whereas both epithelial and stromal cells produce icIL-1ra (type 1 and type 2), the epithelial cells appear to also produce sIL-1ra. It is proposed that these IL-1ra proteins may play an important role in regulating IL-1-induced corneal inflammation.
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PMID:Novel production of interleukin-1 receptor antagonist peptides in normal human cornea. 781 49

In this study, we showed that systemic administration of SSG, a highly branched soluble (1-->3)-beta-D-glucan obtained from Sclerotinia sclerotiorum, induced immunological changes in the alveolar space of mice in vivo, assessed by analysing some immune mediators in bronchoalveolar lavage (BAL) fluid. A single i.v. administration of SSG (250 micrograms/mouse) induced a rapid but transient leakage of the serum components, IgG and fibronectin, into the alveolar space. This was apparent 12 h post-administration and reached a peak on day 2. Similar kinetic changes were found for lysosomal enzyme activities and interferon gamma (IFN gamma) concentrations in BAL which are markers of activated alveolar macrophages (AMs) or pulmonary T cells. BAL prepared from SSG-treated mice stimulated lysosomal enzyme release from AMs in vitro. However, SSG did not provoke the chronic accumulation of serum proteins in alveoli and did not induce the release of detectable amounts of nitric oxide and the inflammatory cytokines, IL-1, IL-6 and TNF alpha, into BAL. However, their mRNAs were detected in lung tissue using the reverse-transcriptase polymerase chain reaction (RT-PCR) technique. Similar results were observed for multiple i.v. administration (250 micrograms, once a day for 10 consecutive days), and there were a little differences between single and multiple administration. In summary, systemic administration of SSG induces immune responses, including activation of AMs and lymphocytes, but does not provoke chronic inflammation in the alveolar space when administered either as single or multiple doses. This finding is very important for the clinical application of SSG in immunocompromised hosts as a biological response modifier (BRM) without toxic-side effects on lung tissue.
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PMID:Changes in immune mediators in mouse lung produced by administration of soluble (1-->3)-beta-D-glucan. 792 Apr 19

Local cytokine gene expression in vivo was analyzed by direct analysis of RNA obtained from salivary gland tissues of MRL/lpr mice with autoimmune sialadenitis. The expression of cytokine genes were assessed by the reverse-transcriptase polymerase chain reaction, and by immunohistochemical analysis. The expression of interleukin-1(IL-1)beta and tumor necrosis factor was detected before the onset of inflammatory lesions in the salivary glands of mice of 1 or 2 months of age, and IL-6 mRNA expression was clearly detected at the time of onset of typical autoimmune sialadenitis at 3 months of age in MRL/lpr mice, and was up-regulated with advancing age. These results suggest that the overexpression of these inflammatory cytokine genes is involved in the development and progression of organ-localized autoimmunity in the salivary glands of MRL/lpr mice.
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PMID:Expressions of cytokine genes during development of autoimmune sialadenitis in MRL/lpr mice. 840 38

The IL-1R antagonist protein (IRAP) is a competitive inhibitor of IL-1, which is predominantly synthesized by monocytes. We show that this molecule is also expressed in human synovial fibroblasts and dermal fibroblasts (CRL 1445). IRAP mRNA was regulated in a time- and dose-dependent manner by IL-1 alpha, TNF-alpha, LPS, and PMA. Maximal induction of IRAP mRNA was observed between 8 and 16 h after stimulation with IL-1 alpha (1 U/ml), TNF-alpha (10 U/ml), LPS (50 ng/ml), and PMA (10 ng/ml). Their relative efficacy was as follows: PMA > LPS > IL-1 alpha > TNF-alpha. Potentiation was observed when fibroblasts were treated with IL-1 alpha plus basic fibroblast growth factor and IL-1 alpha plus platelet-derived growth factor-BB homodimer. Although LPS and PMA were the best inducers of IRAP mRNA, quantitation of the IRAP protein revealed that its synthesis and release were differentially regulated. Immunoprecipitation and SDS-PAGE of culture supernatant from LPS-treated cells and cell lysates of fibroblasts treated with LPS or PMA showed a single IRAP band with a molecular mass of approximately 22 kDa. Very little IRAP was detected in culture supernatants of cells treated with PMA. Quantitation of IRAP revealed that LPS induced the synthesis of secreted IRAP that was released, whereas the majority of the protein induced by PMA remained cell-associated. Reverse transcriptase-polymerase chain reaction amplification demonstrated that although LPS and PMA induced both transcripts, LPS preferentially induced secreted IRAP, whereas PMA differentially induced intracellular IRAP mRNA. Fibroblasts synthesize at least two different forms of IRAP depending on the inducing signal, and may regulate the inflammatory response by dampening the proinflammatory effects of IL-1 via a negative feedback mechanism with IRAP. The relative importance of fibroblast sIRAP vs intracellular IRAP in regulating the inflammatory response by the connective tissue remains to be determined.
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PMID:Regulation of expression of IL-1 receptor antagonist protein in human synovial and dermal fibroblasts. 847 46

There is evidence suggesting the importance of the interleukin-1 receptor type I (IL-1Rtl) and interleukin-1 beta (IL-1 beta) as mediator in local intercellular interactions in endometrial tissue and embryonic implantation. To complete our understanding of the entire endometrial IL-1 system in humans, we have investigated the immunohistochemical distribution of IL-1 receptor antagonist (IL-1ra) in the human endometrium throughout the menstrual cycle. We have also identified the forms of IL-1ra present in human endometrial cells. Immunoreactive IL-1ra was found in both cryostat and paraffin-embedded sections of human endometrium using the alkaline phosphatase-peroxidase (A-P) method with two different IL-1ra antibodies. IL-1ra was present throughout the entire menstrual cycle, located primarily in the endometrial epithelium. However, IL-1ra staining was significantly higher during follicular phase in comparison with early and mid-late luteal phases. Reverse transcriptase polymerase chain reaction of cultured stromal and glandular cells showed that these cells express the intracellular form of IL-1ra mRNA (icIL-1ra). Our results demonstrate the regulated presence of the icIL-1ra in the human endometrium. This finding supports a possible autocrine-paracrine role for the IL-1 system in the human endometrium and embryonic implantation.
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PMID:Immunohistochemical localization, identification and regulation of the interleukin-1 receptor antagonist in the human endometrium. 853 Jun 93

The oral commensal Gram-negative bacterium Actinobacillus actinomycetemcomitans is believed to be the causative organism of localized juvenile periodontitis, a disease in which there is rapid loss of alveolar bone supporting the teeth. Previously, we have reported that gentle saline extraction of this bacterium removed a loosely adherent proteinaceous fraction from the cell surface of the bacterium, which we have termed surface-associated material. This material contained potent bone-resorbing activity. We now report that surface-associated material is also a potent stimulator of cytokines, and in particular, interleukin-6 (IL-6) synthesis, while the lipopolysaccharide from this bacterium is only a weak stimulator of IL-6 synthesis by fibroblasts and monocytes. In contrast to enteric lipopolysaccharide (LPS), which induces fibroblast IL-1, IL-6 and tumour necrosis factor (TNF) alpha synthesis, surface-associated material stimulated gingival fibroblasts to synthesize only IL-6, with no induction of IL-1 or TNF (the normal inducers of IL-6 synthesis). Reverse transcriptase PCR also failed to detect mRNA for IL-1 or TNF in surface-associated-material-stimulated fibroblasts, although both mRNAs were present in Escherichia coli LPS-stimulated cells. Neutralizing antibodies to IL-1 and/or TNF or the natural IL-1 receptor antagonist (IL-1ra) inhibited enteric LPS-induced IL-6 synthesis, but did not inhibit surface-associated-material-induced synthesis. In addition, dexamethasone, which completely suppressed LPS-induced IL-6 synthesis, only inhibited surface-associated-material-induced IL-6 synthesis by 50%. This suggests that the active constituent in the surface-associated material stimulates IL-6 gene transcription by a transcriptional control mechanism distinct to that of E. coli LPS. The IL-6 stimulating activity of the surface-associated material is inhibited by both heat and trypsin, suggesting that it is proteinaceous. The activity has been isolated using anion-exchange, reverse-phase and size-exclusion HPLC. The active moiety is a peptide of molecular mass 2kDa which may be the product of a bacterial short open reading frame.
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PMID:Surface-associated material from the bacterium Actinobacillus actinomycetemcomitans contains a peptide which, in contrast to lipopolysaccharide, directly stimulates fibroblast interleukin-6 gene transcription. 866 8


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