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:4.2.3.23 (GAS)
957 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The induction of CD86 expression by IFN-gamma on the surface of various antigen presenting cells has been previously reported. In order to understand the mechanisms by which the expression of the CD86 gene is regulated by IFN-gamma at the transcriptional level, we have cloned and characterized the 5'-flanking region of the human CD86 gene. To functionally analyze the upstream regulatory region of the CD86 gene, a series of luciferase reporter gene constructs were prepared and used for transfection of cells from the monocytic line U937 and Raji B cell line. Under basal conditions, functional activity of these constructs was detected in Raji cells, which show high constitutive expression of the CD86 molecule, but not in U937 cells, which show low expression of CD86 in non-activated state. Induction of CD86 expression by stimulation of U937 cells with IFN-gamma revealed the presence of two functional GAS (gamma-interferon activation site) elements. Gel mobility shift assays showed that these two GAS elements specifically bind an IFN-gamma-induced transcriptional complex. The DNA-protein complex was supershifted by antibody to Stat1 alpha (signal transducer and activator of transcription), but not by antibodies to Stat 2, Stat 3 and Sp1, indicating that GAS elements interact with Stat1 alpha. Point mutations in the GAS elements prevented the formation of DNA-protein complex and significantly reduced the responsiveness of the reporter gene to IFN-gamma. These findings suggest that two functional GAS elements within the human CD86 promoter play an important role in the induction of CD86 gene by binding to IFN-gamma-induced Stat1 alpha.
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PMID:Cloning and functional characterization of the 5'-regulatory region of the human CD86 gene. 1077 51

The present study was carried out to gain insight into the mechanisms involved in the pathogenesis of streptococcal toxic shock syndrome (TSS) and other acute invasive diseases caused by Streptococcus pyogenes (GAS). Specifically, since both whole bacteria and their soluble products are often present in the blood in these conditions, we sought to detect possible synergic activities of somatic and extracellular products in inducing mediators release. For this purpose, whole blood cultures from healthy donors were incubated with different concentrations of streptococcal pyrogenic exotoxin A (SpeA), which is considered a major molecular effector of TSS, heat-killed GAS and cell-wall components such as lipoteichoic acid (LTA) and soluble peptidoglican (sPGN). Significant levels of TNF-alpha, IL-1 alpha and IFN-gamma were found in supernatants from cultures incubated with each of the four inducers alone. Whole GAS and both cell-wall components were more effective (p < 0.05) than SpeA in inducing cytokine release. Whole GAS, at weight basis, was a more potent inducer than LTA and sPGN and LTA, at weight basis, was a more potent inducer than sPGN. In order to verify possible additive or synergic effects of exotoxic and parietal compounds in inducing cytokine release, whole blood cells were incubated with mixtures of SpeA and LTA at different molecular ratio. TNF-alpha, IL-1 alpha and IFN-gamma levels in supernatants were significantly (p < 0.05) higher in supernatants of cultures stimulated simultaneously with the two components than those of cultures stimulated with a single agent. Moreover, these levels were significantly higher than the sum of cytokine levels induced by single components. This study shows that parietal compounds can act in synergy with exotoxins in inducing the release of cytokines, which appear to be the major mediators of TSS.
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PMID:Synergic activities of streptococcal pyrogenic exotoxin A and lipoteichoic acid in cytokine induction. 1094 4

The vasoactive intestinal peptide (VIP) and the pituitary adenylate cyclase-activating polypeptide (PACAP), two immunomodulatory neuropeptides that affect both innate and acquired immunity, down-regulate IL-12 p40 and inducible NO synthase expression in LPS/IFN-gamma-stimulated macrophages. We showed previously that VIP/PACAP inhibit NF-kappaB nuclear translocation through the stabilization of IkappaB and reduce IFN regulatory factor-1 (IRF-1) binding to the regulatory elements found in the IL-12 p40 and inducible NO synthase promoters. In this paper we studied the molecular mechanisms involved in the VIP/PACAP regulation of IRF-1 transactivating activity. Our studies indicate that the inhibition in IRF-1 binding correlates with a reduction in IRF-1 protein and mRNA in IFN-gamma-treated Raw 264.7 macrophages. In agreement with the described Janus kinase (Jak)1/Jak2/STAT1/IRF-1 activation pathway, VIP/PACAP inhibit Jak1/Jak2, STAT1 phosphorylation, and the binding of STAT1 to the GAS sequence motif in the IRF-1 promoter. The effects of VIP/PACAP are mediated through the specific VIP/PACAP receptor-1 and the cAMP/protein kinase A (PKA) transduction pathway, but not through the induction of suppressor of cytokine signaling-1 or suppressor of cytokine signaling-3. Because IFN-gamma is a major stimulator of innate immune responses in vivo, the down-regulation of IFN-gamma-induced gene expression by VIP and PACAP could represent a significant element in the regulation of the inflammatory response by endogenous neuropeptides.
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PMID:Inhibition of IFN-gamma-induced janus kinase-1-STAT1 activation in macrophages by vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide. 1097 15

The radical nitric oxide (NO) constitutes an important part of the innate immune response to many viruses, and among these notably Herpes simplex virus (HSV). We have previously shown that HSV/tumor necrosis factor-alpha (TNF-alpha) and IFN-gamma synergistically induce NO production in macrophages, and here we have investigated the molecular mechanism underlying this phenomenon. The enhancement of NO production was regulated at the level of NO synthase 2 (NOS2, iNOS) transcription. The ISRE element of the NOS2 promoter, which binds IFN regulatory factor (IRF)-1, was essential both for full responsiveness to IFN-gamma and the synergistic response. The GAS motif, binding signal transducer and activator of transcription 1 (STAT1), did not contribute to the cross-talk with virus/TNF-induced signals, but was necessary for full responsiveness to IFN-gamma. The distal binding site for nuclear factor (NF)-kappa B was important for the cooperative response, while the proximal kappa B site was not involved in the cooperative promoter activation but played a role in full promoter inducibility. By ectopic expression of IRF-1 and NF-kappa B (p65), we found that these factors synergistically induce NO accumulation. Together, our results show that binding of IRF-1 and NF-kappa B to their respective sites in the distal domain of the NOS2 promoter, creates a potent trans-activating complex with the ability to induce NOS2 transcription synergistically in response to simultaneous HSV-2/TNF-alpha and IFN-gamma treatment.
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PMID:Interferon (IFN)-gamma and Herpes simplex virus/tumor necrosis factor-alpha synergistically induce nitric oxide synthase 2 in macrophages through cooperative action of nuclear factor-kappa B and IFN regulatory factor-1. 1139 19

Class II transactivator (CIITA) is required for both constitutive and inducible expression of MHC class II genes. IFN-gamma induced expression of CIITA in various cell types is directed by CIITA type IV promoter. The two transactivators, STAT1 and IRF-1, mediate the IFN-gamma activation of the type IV promoter by binding to the GAS and IRF-E of the promoter, respectively. In addition to IRF-1, IRF-2, another member of the IRF family, also activates the human CIITA type IV promoter, and IRF-2 cooperates with IRF-1 to activate the promoter in transient transfection assays. IRF-1 and IRF-2 can co-occupy the IRF-E of the human CIITA type IV promoter. To understand the effect of loss of IRF-2 on the endogenous CIITA expression, we assayed for CIITA expression in IRF-2 knock-out mice. Both basal and IFN-gamma induced CIITA expression were reduced in IRF-2 knock-out mice. At least half of the amount of inducible CIITA mRNA depends on IRF-2. The reduction of IFN-gamma induced CIITA mRNA in IRF-2 knock-out mice was due to the reduction of the type IV CIITA mRNA induction. The reduction of basal CIITA mRNA was apparently due to the reduction of CIITA mRNA originating from other promoters. These data indicate that IRF-2, like IRF-1, plays a critical role in the regulation of the endogenous CIITA gene. The implications in understanding the previously described phenotypes of IRF-2 defective mice are discussed.
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PMID:Impaired class II transactivator expression in mice lacking interferon regulatory factor-2. 1146 88

IFN-gamma induced transcription of class II transactivator (CIITA), a major regulator of MHC class II gene expression, is directed by the CIITA type IV promoter. The IFN-gamma activation of the CIITA type IV promoter is mediated by STAT1 and IRF-1, which bind to the GAS and IRF-E of the promoter, respectively. We and others have determined that IRF-2, another member of the IRF family, also activates the CIITA type IV promoter, by binding to the IRF-E. Also, IRF-2 cooperates with IRF-1 to activate the promoter. DNA binding analyses determined that IRF-1 and IRF-2 can co-occupy the IRF-E of the CIITA type IV promoter. To further understand the mechanism of IRF-1 and IRF-2 cooperativity in the activation of CIITA type IV promoter, we characterized the binding of IRF-1 and IRF-2 to the CIITA IRF-E and mapped the domains of IRF-2 required for the cooperative transactivation. Off-rate experiments revealed that the IRF-2/IRF-E complex was more stable than the IRF-1/IRF-E complex and that the affinity of IRF-1 for the IRF-E was increased when IRF-1 co-occupied the IRF-E with IRF-2. Deletion analysis of functional domains of IRF-2 revealed that a previously described latent activation domain of IRF-2 was essential for IRF-2 transactivation and participated in cooperative activation of the CIITA promoter by IRF-1 and IRF-2. However, the DNA binding domain of IRF-2 was sufficient for cooperativity with IRF-1 in the activation of the CIITA type IV promoter. DNA binding assay demonstrated that, like the full-length IRF-2, the IRF-2 DNA binding domain could co-occupy the CIITA IRF-E with IRF-1.
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PMID:The IRF-2 DNA binding domain facilitates the activation of the class II transactivator (CIITA) type IV promoter by IRF-1. 1249 43

The short chain fatty acid butyrate promotes proliferation and survival of normal epithelial cells, but induces G(1) or G(2)-M arrest in transformed cells, which is coupled to differentiation and apoptosis. Local administration of butyrate has been shown to ameliorate inflammation in ulcerative colitis; however, the precise mechanism of its anti-inflammatory activity is not known. IFN-gamma is one of the principle cytokines secreted by lamina propria cells in inflamed mucosa and elevated levels of the transcription factor required for IFN-gamma signaling, STAT1 (signal transducer and activator of transcription 1), are present in the colonic mucosa of patients with ulcerative colitis and Crohn's disease. Here we report that butyrate is a strong inhibitor of signaling by IFN-gamma. We demonstrated that this short chain fatty acid inhibits IFN-gamma-induced tyrosine and serine phosphorylation of STAT1. IFN-gamma-induced JAK2 activation was inhibited by butyrate, implicating JAK2 as a target of butyrate action. Accordingly, STAT1 nuclear translocation and its DNA binding were completely inhibited in butyrate-treated cells. Transient transfection experiments using a reporter gene construct containing eight GAS sites (gamma-activated sites) revealed that butyrate inhibits IFN-gamma induced, STAT1-dependent, transcriptional activation. Proinflammatory cytokines, including IFN-gamma, play an important role in the pathogenesis of inflammatory bowel disease, and abnormal activity of STAT1 is associated with human malignancies and intestinal inflammatory diseases. Thus, our data suggest that butyrate negatively regulates mucosal inflammation through the inhibition of IFN-gamma/STAT1 signaling.
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PMID:Inhibition of interferon gamma signaling by the short chain fatty acid butyrate. 1451 48

CD94 is a C-type lectin required for the dimerization of the CD94/NKG2 family of receptors, which are expressed on NK cells and T cell subsets. Little is known about CD94 gene expression and the elements that regulate CD94 transcription. In this study, we report that CD94 gene expression is regulated by distal and proximal promoters that transcribe unique initial exons specific to each promoter. This results in two species of transcripts; the previously described CD94 mRNA and a novel CD94C mRNA. All NK cells and CD94(+), CD8(+) alphabeta T cells transcribe CD94 mRNA. Stimulation of NK and CD8(+) alphabeta T cells with IL-2 or IL-15 induced the transcription of CD94C mRNA. The distal and proximal promoters both contain elements with IFN-gamma-activated and Ets binding sites, known as GAS/EBS. Additionally, an unknown element, termed site A, was identified in the proximal promoter. EMSA analyses showed that constitutive factors could bind to oligonucleotide probes containing each element. After treatment of primary NK cells with IL-2 or IL-15, separate inducible complexes could be detected with oligonucleotide probes containing either the proximal or distal GAS/EBS elements. These elements are highly conserved between mice and humans, which suggests that both species regulate CD94 gene expression via mechanisms that predate their evolutionary divergence.
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PMID:Human CD94 gene expression: dual promoters differing in responsiveness to IL-2 or IL-15. 1460 29

Protein kinase C-theta (PKC-theta) plays important roles in the activation and survival of lymphocytes and is the predominant PKC isoform expressed in T-cells. Interferons regulate T-cell function and activation, but the precise signaling mechanisms by which they mediate such effects have not been elucidated. We determined whether PKC-theta is engaged in interferon (INF) signaling in T-cells. Both Type I (alpha, beta) and Type II (gamma) IFNs induced phosphorylation of PKC-theta in human T-cell lines and primary human T-lymphocytes. Such phosphorylation of PKC-theta resulted in activation of its kinase domain, suggesting that this kinase plays a functional role in interferon signaling. Consistent with this, inhibition of PKC-theta protein expression using small interfering RNAs (siRNA) abrogated IFN-alpha- and IFN-gamma-dependent gene transcription via GAS elements. Similarly, blocking of PKC-theta kinase activity by overexpression of a dominant-negative PKC-theta mutant also blocked GAS-driven transcription, further demonstrating a requirement for PKC-theta in IFN-dependent transcriptional activation. The effects of PKC-theta on IFN-dependent gene transcription were not mediated by regulation of the IFN-activated STAT pathway, as siRNA-mediated PKC-theta knockdown had no effects on STAT1 phosphorylation and binding of STAT1-containing complexes to SIE/GAS elements. On the other hand, siRNA-mediated PKC-theta inhibition blocked phosphorylation/activation of MKK4, suggesting that interferon-dependent PKC-theta activation regulates downstream engagement of MAP kinase pathways. Altogether, these findings demonstrate that PKC-theta is an interferon-inducible kinase and strongly suggest that it plays an important role in the generation of interferon-responses in T-cells.
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PMID:Engagement of protein kinase C-theta in interferon signaling in T-cells. 1515 Feb 72

Trapidil is a triazolopyrimidine that has been found to prevent restenosis after vascular injury. Although its precise mode of action is still unclear, several biological effects have been described including inhibition of IFN-gamma-induced CD40 expression on monocytes. Herein, we investigated the molecular mechanisms by which Trapidil exerts this inhibitory action. First, we observed that the inhibition of CD40 expression is associated with the suppression of CD40 gene transcription, as demonstrated by a clear decrease of CD40 nuclear RNA (nRNA) levels and unchanged CD40 mRNA half-life. IFN-gamma-induced CD40 transcription has been shown to be mediated by STAT1alpha dimers (p91/p84) which, after nuclear translocation, bind to GAS elements present in the promoter of IFN-gamma responsive genes. Electrophoresis mobility shift assay (EMSA) with both STAT1 consensus and CD40 mGAS probes showed that Trapidil did not affect the DNA binding ability of STAT1 dimers. STAT1 dimerization and activation are conferred by upstream phosphorylation of two amino acid residues of the STAT1 protein. The subsequent studies on these two potential STAT1 phosphorylation sites (Tyr701, Ser727) revealed that Trapidil attenuated IFN-gamma-induced Ser727 but not Tyr701 phosphorylation. The inhibition of CD40 transcription by Trapidil could at least partially owing to the impaired Ser727 phosphorylation of STAT1, since IFN-gamma failed to trigger CD40 expression in U3A S727A cells, a cell line displaying a point mutation at the Ser727 site. Collectively, our results indicate that phosphorylation of STAT1 at the Ser727 site enhances CD40 transcription and that Trapidil might be used as a selective inhibitor that could differentially modulate STAT1 target genes.
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PMID:Trapidil inhibits monocyte CD40 expression by preventing IFN-gamma-induced STAT1 S727 phosphorylation. 1518 26


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