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 incidence of severe invasive disease caused by serogroup A streptococci (GAS) is increasing, and to elucidate the role of streptococcal cell wall components in the inflammatory response, human whole blood was stimulated with lipoteichoic acid (LTA, 0.005-50 microg/mL) and peptidoglycan (10 and 100 microg/ml) from Streptococcus pyogenes. Both stimulants increased dose dependently the leukocyte release of cytokines many thousand fold: tumor necrosis factor alpha (0 to 158,000+/-4,900 pg/mL), interleukin (IL)-1beta (85+/-56 to 31,000+/-4,600 pg/mL), IL-6 (30+/-11 to 34,800+/-15,000 pg/mL), and IL-8 (300+/-150 to 29,000+/-14,000 pg/mL). Intracellular leukocyte levels of reactive oxygen species (ROS) as measured by flow cytometry increased 15-20 fold, from 25 to 400-500 mean fluorescence intensity. Aminoethyl-isothiourea (AE-ITU), a relatively selective inhibitor of the inducible nitric oxide synthase (iNOS) and a ROS scavenger, reduced the cytokine production by 70-100%, and intracellular leukocyte ROS levels by 50-70% (all P < 0.05). The non-selective NOS inhibitor N-nitro-L-arginine methyl ester (L-NAME) did not affect intracellular ROS levels, but it caused a moderate selective inhibition of IL-8 production. Leukocyte NO production (measured up to 36 h) was not enhanced by LTA, peptidoglycan, inactivated streptococci, or cytokine combinations. The mechanisms for the anti-inflammatory effects of AE-ITU may be through a reduction of intracellular ROS levels, or through a direct effect on signal transduction, whereas NO modulation is an unlikely mechanism.
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PMID:Aminoethyl-isothiourea inhibits leukocyte production of reactive oxygen species and proinflammatory cytokines induced by streptococcal cell wall components in human whole blood. 1138 18

1. In this study we examined the signalling events that regulate lipopolysaccharide (LPS)-stimulated induction of interferon regulatory factor (IRF)-1 in human umbilical vein endothelial cells (HUVECs). 2. LPS stimulated a time- and concentration-dependent increase in IRF-1 protein expression, an effect that was mimicked by the cytokine, tumour necrosis factor (TNF)-alpha. 3. LPS stimulated a rapid increase in nuclear factor kappa B (NFkappaB) DNA-binding activity. Pre-incubation with the NFkappaB pathway inhibitors, N-alpha-tosyl-L-lysine chloromethyl ketone (TLCK) or pyrrolidine dithiocarbamate (PDTC), or infection with adenovirus encoding IkappaBalpha, blocked both IRF-1 induction and NFkappaB DNA-binding activity. 4. LPS and TNFalpha also stimulated a rapid activation of gamma interferon activation site/gamma interferon activation factor (GAS/GAF) DNA-binding in HUVECs. Preincubation with the Janus kinase (JAK)-2 inhibitor, AG490 blocked LPS-stimulated IRF-1 induction but did not affect GAS/GAF DNA-binding. 5. Preincubation with TLCK, PDTC or infection with IkappaBalpha adenovirus abolished LPS-stimulated GAS/GAF DNA-binding. 6. Incubation of nuclear extracts with antibodies to RelA/p50 supershifted GAS/GAF DNA-binding demonstrating the involvement of NFkappaB isoforms in the formation of the GAS/GAF complex. 7. These studies show that NFkappaB plays an important role in the regulation of IRF-1 induction in HUVECs. This is in part due to the interaction of NFkappaB isoforms with the GAS/GAF complex either directly or via an intermediate protein.
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PMID:Nuclear factor kappa B is involved in lipopolysaccharide-stimulated induction of interferon regulatory factor-1 and GAS/GAF DNA-binding in human umbilical vein endothelial cells. 1173 38

The ability of the testis to convert irreversibly androgens into estrogens is related to the presence of a microsomal enzymatic complex named aromatase. Although somatic cells and germ cells (GC) have the capacity to produce estrogens the regulation of the CYP19 gene expression in adult rat testicular cells and specially in freshly purified Leydig cells, pachytene spermatocytes (PS) and round spermatids (RS) is not fully understood. In the present study we have analyzed the putative effects of steroid hormones, transforming growth factor beta (TGFbeta), cytokine (tumor necrosis factor alpha, TNFalpha) and dexamethasone (Dex) on CYP19 expression in these purified testicular cells from adult rat. In parallel the biological role of seminiferous tubules and Sertoli cells conditioned media on the expression of aromatase was studied. Using a highly specific quantitative competitive RT-PCR we established that testosterone (T) enhances CYP19 gene expression in Leydig cells and germ cells, and augments the estradiol outputs. The non-aromatizable androgen 5alpha-DHT induces the same effect as T on P450 aromatase (P450arom) gene expression but was inefficient on the estradiol output. In PS and RS an inhibitory effect on CYP19 gene transcription was observed with TGFbeta (1 ng/ml) alone or in combination with T. Conversely, the addition of TNFalpha (20 ng/ml) increases the P450arom transcription in PS although an inhibitory effect is observed in RS. Together with T, TNFalpha decreases the amount of P450arom mRNA in PS and RS. In PS we found that Dex regulates positively CYP19 expression and negatively in RS. Furthermore in PS a synergistic effect of Dex and TNFalpha on P450arom mRNA expression was observed whereas an additive one was recorded for RS. Therefore in germ cells TNFalpha likely enhances expression of aromatase through promoter PI.4 in PS, possibly via an AP1 site upstream the GAS element, while in RS TNFalpha requires glucocorticoids as a co-stimulator to increase CYP19 gene expression. Finally in presence of seminiferous tubules or Sertoli cell conditioned media, the amount of aromatase transcripts is increased in both Leydig cells and germ cells therefore suggesting that other locally produced modulators, yet unknown, but from Sertoli cell origin, are concerned in the regulation of the aromatase gene expression in rat testicular cells. In summary, using an in vitro model of mature rat Leydig cells, pachytene spermatocytes and round spermatids, we have shown that several factors direct the expression of the aromatase gene and it is obvious that not only promoter PII but also promoter PI.4 are concerned.
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PMID:Regulation of aromatase gene expression in Leydig cells and germ cells. 1462 30

Arsenic trioxide (As2O3) can induce clinical remission in patients with acute promyelocytic leukemia (APL), including those who have relapsed after treatment with all-trans-retinoic acid (RA). In vitro studies with the APL-derived NB4 cell line showed that As2O3 exerts a dose-dependent dual effect, which induces apoptosis at 1 microM, whereas at a lower concentration of 0.1 microM, a partial differentiation of APL is observed. In non-APL cells, interferon (IFN) alpha and 1 microM As2O3 act synergistically to induce apoptosis. In this report, we show that in NB4 cells and in two RA-resistant NB4-derived cell lines, NB4-R1 and NB4-R2, IFNalpha or IFNgamma combined with 0.1 microM As2O3 lead to an increased maturation effect. Moreover, IFNgamma alone is able to differentiate RA-sensitive and -resistant cells with a higher maturation effect on NB4-R2 cells. In contrast, all these cells underwent apoptosis in the presence of the cytokine and a higher concentration of As2O3. IFNgamma boosted As2O3-induced apoptosis in APL cells as tested by TUNEL, Annexin V staining and activation of caspase 3. As2O3 differently altered IFN-induced gene products; it downregulated PML/RARalpha and PML, did not alter PKR and Stat1, and upregulated interferon regulatory family (IRF)-1. Synergism by IFNgamma and arsenic on IRF-1 expression is mediated by a composite element in the IRF-1 promoter that includes an IFNgamma-activation site (GAS) overlapped by a nonconsensus site for nuclear factor kappa B (NFkappaB). Arsenic has no effect on NFkappaB, whereas it enhances the activation of Stat1 by IFNgamma in NB4 cells leading to an increase in IRF-1 expression.
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PMID:Arsenic enhances the activation of Stat1 by interferon gamma leading to synergistic expression of IRF-1. 1466 93

Previously we have reported that thrombin induces inflammatory mediators in brain glial cells (Ryu et al. 2000. J Biol Chem 275:29955). In the present study, we found that thrombin induced a negative regulator of a cytokine signaling molecule, cytokine-induced SH2 protein (CIS), in rat brain astrocytes. In response to thrombin, CIS expression was increased at both the mRNA and protein levels. Although STAT5 is known to regulate CIS expression, thrombin did not activate STAT5, and inhibitors of JAK2 (AG490) and JAK3 (WHI-P97 and WHI-P154) had little effect on thrombin-induced CIS expression. In contrast, cytosolic phospholipase A(2) (cPLA(2)), cyclooxygenase (COX), and lipoxygenase (LO) play a role in CIS expression, since inhibitors of cPLA(2), cyclooxygenase (COX), and LO significantly reduced CIS expression. Reactive oxygen species (ROS) scavengers (N-acetyl-cysteine [NAC] and trolox) reduced thrombin-induced CIS expression, and inhibitors of COX and LO reduced ROS produced by thrombin. Furthermore, prostaglandin E(2) (PGE(2)) and leukotriene B(4) (LTB(4)), products of COX and LO, respectively, potentiated thrombin-induced CIS expression, indicating that ROS, and PGE(2) and LTB(4) generated by COX and LO, mediate CIS expression. Since interferon-gamma (IFN-gamma)-induced GAS-luciferase activity and tyrosine phosphorylation of STAT1 and STAT3 were lower in CIS-transfected cells compared to control vector-transfected cells, CIS could have anti-inflammatory activity. These data suggest that thrombin-stimulation of ROS and prostaglandin and leukotriene production via the cPLA(2), COX and LO pathways results in CIS expression. More importantly, CIS expression may be a negative feedback mechanism that prevents prolonged inflammatory responses.
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PMID:Thrombin induces expression of cytokine-induced SH2 protein (CIS) in rat brain astrocytes: involvement of phospholipase A2, cyclooxygenase, and lipoxygenase. 1537 59

Many leukemia and cancer cells exhibit constitutive activation of STAT5, which was suggested to provide an anti-apoptotic advantage. Transformation of cytokine-dependent hematopoietic cells, such as Ba/F3 cells to autonomous growth and tumorigenicity equally results in selection for constitutive activation of STAT5. We compared STAT5 signaling between erythropoietin(Epo)-dependent cells and cells that were transformed by oncogenic activation of the erythropoietin receptor (EpoR) by coexpression of the gp55-P envelope protein of the spleen focus forming virus or by expression of the R129C constitutively active EpoR mutant. In transformed cells it was mainly STAT5B that was constitutively activated. In contrast, Epo stimulation activated both STAT5A and STAT5B. In transformed cells, chromatin immunoprecipitation (ChIP) showed STAT5 to be physically bound to promoters of STAT5 target genes, such as Bcl(XL), and to be able to promote transactivation of the Bcl(XL) promoter in a constitutive fashion. Sequencing of native sequences after ChIP with anti-STAT5 antibodies in Epo-dependent and -transformed cells indicated that in gp55-transformed cells, STAT5B bound in the chromatin not only to N3 high affinity, but also to low affinity N4 GAS sites. Transactivation for N3 GAS sites in luciferase reporters was specific to gp55 transformation. Because we also found preferential constitutive STAT5B activation after transformation of cells by a truncated form of the G-CSF-R that produces severe neutropenia (Kostmann syndrome) and favors leukemia in humans, we discuss the potential role of STAT5B in oncogenic transformation of hematopoietic cells.
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PMID:Differential STAT5 signaling by ligand-dependent and constitutively active cytokine receptors. 1567 77

The bacterial human pathogen Streptococcus pyogenes (group A streptococci, GAS) is able to adhere to, internalize into and cross-talk on multiple levels with its host cells. To gain insight into the Fas function in pathogenesis we used Affymetrix human genome DNA-arrays to measure temporal and global transcriptional responses of HEp-2 cells infected with M49 S. pyogenes wild-type bacteria and DeltafasX, an isogenic S. pyogenes two-component-signal-transduction system mutant. A modified stringent statistical analysis method identified a total of 86 HEp-2 cell genes as differentially transcribed upon infection over the investigated time course. Increased expression of genes encoding proteins involved in GAS host cell adherence and internalization (fibronectin, integrin-alpha5) was found as a common response. In contrast to earlier reports investigating other GAS serotype strains, Ras superfamily and RhoA pathways are exploited by M49 GAS, suggesting serotype specific interactions with the host cell cytoskeleton. Despite transcriptional induction, secreted IL-8 levels of deltafasX mutant infected cells were below those of non-infected cells, indicating an absence of Fas expression could be important for GAS tissue colonization and long-term intracellular persistence. Oppositely, activity of the S. pyogenes Fas-system apparently promotes high adherence and internalization rates, massive cytokine gene transcription and cytokine release, host cell apoptosis via a caspase-2 activation pathway, and cytotoxicity. Thus, the S. pyogenes Fas two-component signal transduction system could be involved in local tissue destruction and general bacterial aggressiveness towards host cells.
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PMID:Global epithelial cell transcriptional responses reveal Streptococcus pyogenes Fas regulator activity association with bacterial aggressiveness. 1609 12

The severity of infection with Streptococcus pyogenes is strongly influenced by the host's genetics. This observation extends to the murine model of streptococcal infection, where the background of the mouse strain determines the infection outcome (BALB/c are resistant, whereas C3H/HeN are susceptible). To determine the extent to which the MHC complex (H2) contributed to diseases susceptibility, the response to S. pyogenes of congenic BALB mice from a resistant background (BALB/c), but carrying the H2(k) region of susceptible C3H/HeN mice (BALB/k), was examined. BALB/k were as susceptible as the H2 donor strain (C3H/HeN). Linkage analysis performed in F(2) backcross ([BALB/c x C3H/HeN] x BALB/c) mice confirmed the presence of a susceptibility locus within the H2 region on proximal chromosome 17. The possibility that modulation of T cell responses to streptococcal superantigens (GAS-SAgs) by different H2 haplotypes may influence disease severity was examined. BALB/k exhibited a significantly stronger response at the level of cell proliferation and cytokine production to GAS-SAgs than did BALB/c mice. However, the fact that T cell-deficient SCID-C3H/HeN mice also exhibited a susceptible phenotype suggests a more important contribution of innate effector cells to disease susceptibility. Lower transcriptional levels of certain inflammation-related regulatory genes located on chromosome 17 were detected in macrophages from susceptible than in those from resistant mice in response to infection. These results suggest that susceptibility to S. pyogenes may be associated with an altered transcription of specific genes that may compromise the endogenous regulatory processes controlling the inflammatory cascade and favor the progression to sepsis.
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PMID:The role of the MHC on resistance to group a streptococci in mice. 1614 32

Costimulation between T cells and antigen-presenting cells is required for adaptive immune responses. CD40, a costimulatory molecule, is expressed in macrophages and microglia. The aberrant expression of CD40 is involved in human diseases including multiple sclerosis, rheumatoid arthritis, and Alzheimer's disease. CD40 expression is induced by a variety of stimuli, including IFN-gamma and lipopolysaccharide (LPS). In this study, we describe the molecular basis by which IFN-beta, a cytokine with immunomodulatory properties, regulates CD40 gene expression. IFN-beta induces CD40 expression in macrophages and microglia at the transcriptional level, and GAS elements in the CD40 promoter are required for IFN-beta-induced CD40 promoter activity. The critical role of signal transducers and activators of transcription-1alpha (STAT-1alpha) in this response was confirmed by utilizing primary microglia from STAT-1alpha deficient mice. IFN-beta induces suppressor of cytokine signaling-1 (SOCS-1) gene expression, which inhibits cytokine signaling by inhibiting activation of STAT proteins. The ectopic expression of SOCS-1 abrogates IFN-beta-mediated STAT-1alpha activation and inhibits IFN-beta-induced CD40 expression. IFN-beta-induced recruitment of STAT-1alpha and RNA Pol II and permissive histone modifications on the CD40 promoter are also inhibited by SOCS-1 overexpression. These novel results indicate that IFN-beta-induced SOCS-1 plays an important role in the negative regulation of IFN-beta-induced CD40 gene expression.
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PMID:IFN-beta-induced SOCS-1 negatively regulates CD40 gene expression in macrophages and microglia. 1657 71

Induction of nitric oxide synthase-2 (iNOS) by cytokines and bacterial products is associated with protein binding at the proximal promoter and in an upstream enhancer region of the Nos2 gene. To clarify how ethanol suppresses rat iNOS activity, we constructed several deletion mutants of the Nos2 promoter fused to the luciferase gene and transfected the constructs into C6 glial cells. Acute ethanol exposure of stably transfected cells for 24 h inhibits induced activity of Nos2 promoter constructs containing deletions in the 5' flanking region, including a 94 bp promoter that lacks any known NF-kappaB site but which carries a C/EBPbeta and overlapping gamma-IRE, GAS and Oct motifs. Ethanol failed to inhibit the endogenous activity of a smaller, 78 bp promoter that lacks the C/EBPbeta and overlapping, gamma-IRE and GAS motifs and showed no inducible activity. As another approach, in vivo DNA footprinting was used and identified protein protections at five regions of the proximal Nos2 promoter in induced cells. Exposure to acute ethanol diminished protein occupation in the five promoter regions including the gamma-IRE/NF-kappaB and the overlapping gamma-IRE/GAS/Oct sites. Site-directed mutagenesis in the octamer domain of the gamma-IRE/GAS/Oct motifs was studied in a 1002 bp promoter to examine its role in ethanol inhibition of cytokine and lipopolysaccharide induced activity. The data indicate that ethanol failed to inhibit promoter activity when the Oct motif is missing. Electrophoretic mobility shift assays performed using a 22-mer probe containing the overlapping gamma-IRE/GAS/Oct sites showed three complexes with one of the complexes being competed by an octamer-1 antibody. These observations demonstrate the role of protein-DNA binding at the core promoter, and the likely involvement of the octamer motif, in ethanol modulation of cytokine and lipopolysaccharide induced iNOS expression.
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PMID:The Oct DNA motif participates in the alcohol inhibition of the inducible nitric oxide synthase gene promoter in rat C6 glioma cells. 1793 31


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