scholarly journals Inhibition of Response to Alpha Interferon by Mycobacterium tuberculosis

2003 ◽  
Vol 71 (5) ◽  
pp. 2487-2497 ◽  
Author(s):  
Savita Prabhakar ◽  
Yaming Qiao ◽  
Yoshihiko Hoshino ◽  
Michael Weiden ◽  
Antony Canova ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Tyrosine Phosphorylation ◽  
Pathogenic Bacteria ◽  
Binding Activity ◽  
Regulation Of Transcription ◽  
Dna Binding Activity ◽  
Transcription Factor Activation ◽  
Monocytes And Macrophages ◽  
The Impact ◽  
Stimulation Of

ABSTRACT We previously reported that infection by Mycobacterium tuberculosis, the causative agent of tuberculosis, leads to secretion of alpha/beta interferon (IFN-α/β). While IFN-α/β ordinarily stimulates formation of signal transducer and stimulator of transcription-1 (STAT-1) homodimers and IFN-stimulated gene factor-3 (ISGF-3), only ISGF-3 is found in infected human monocytes and macrophages. We have now investigated the basis for this unusual profile of transcription factor activation and its consequences for regulation of transcription, as well as the impact of infection on response to IFN-α. After infection, IFN-α stimulation of STAT-1 homodimers is inhibited in monocytes and macrophages, while stimulation of ISGF-3 increases in monocytes but tends to decline in macrophages. Effects of infection on the abundance of ISGF-3 subunits, STAT-1, STAT-2, and interferon regulatory factor 9, and on tyrosine phosphorylation of STAT-1 and STAT-2 explain the observed changes in DNA-binding activity, which correlate with increased or inhibited transcription of genes regulated by ISGF-3 and STAT-1. Infection by Mycobacterium bovis BCG does not inhibit IFN-α-stimulated tyrosine phosphorylation of STAT-1, formation of homodimers, or transcription of genes regulated by STAT-1 homodimers, suggesting that inhibition of the response to IFN-α/β by M. tuberculosis is an aspect of pathogenicity. Thus, this well-known feature of infection by pathogenic viruses may also be a strategy employed by pathogenic bacteria.

scholarly journals Toll-Like Receptor Stimulation Induces Nondefensin Protein Expression and Reverses Antibiotic-Induced Gut Defense Impairment

2014 ◽  
Vol 82 (5) ◽  
pp. 1994-2005 ◽  
Author(s):  
Ying-Ying Wu ◽  
Ching-Mei Hsu ◽  
Pei-Hsuan Chen ◽  
Chang-Phone Fung ◽  
Lee-Wei Chen
Keyword(s):  
Dna Binding ◽  
Protein Expression ◽  
Antibiotic Treatment ◽  
Intestinal Mucosa ◽  
Pathogenic Bacteria ◽  
Binding Activity ◽  
Toll Like Receptor ◽  
Content Type ◽  
Killing Activity ◽  
Dna Binding Activity

ABSTRACTPrior antibiotic exposure is associated with increased mortality in Gram-negative bacteria-induced sepsis. However, how antibiotic-mediated changes of commensal bacteria promote the spread of enteric pathogenic bacteria in patients remains unclear. In this study, the effects of systemic antibiotic treatment with or without Toll-like receptor (TLR) stimulation on bacterium-killing activity, antibacterial protein expression in the intestinal mucosa, and bacterial translocation were examined in mice receiving antibiotics with or without oral supplementation of deadEscherichia coliorStaphylococcus aureus. We developed a systemic ampicillin, vancomycin, and metronidazole treatment protocol to simulate the clinical use of antibiotics. Antibiotic treatment decreased the total number of bacteria, including aerobic bacteria belonging to the familyEnterobacteriaceaeand the genusEnterococcusas well as organisms of the anaerobic generaLactococcusandBifidobacteriumin the intestinal mucosa and lumen. Antibiotic treatment significantly decreased the bacterium-killing activity of the intestinal mucosa and the expression of non-defensin-family proteins, such as RegIIIβ, RegIIIγ, C-reactive protein-ductin, and RELMβ, but not the defensin-family proteins, and increasedKlebsiella pneumoniaetranslocation. TLR stimulation after antibiotic treatment increased NF-κB DNA binding activity, nondefensin protein expression, and bacterium-killing activity in the intestinal mucosa and decreasedK. pneumoniaetranslocation. Moreover, germfree mice showed a significant decrease in nondefensin proteins as well as intestinal defense against pathogen translocation. Since TLR stimulation induced NF-κB DNA binding activity, TLR4 expression, and mucosal bacterium-killing activity in germfree mice, we conclude that the commensal microflora is critical in maintaining intestinal nondefensin protein expression and the intestinal barrier. In turn, we suggest that TLR stimulation induces nondefensin protein expression and reverses antibiotic-induced gut defense impairment.

scholarly journals Modulation of DNA-binding activity of Mycobacterium tuberculosis HspR by chaperones

Microbiology ◽  
2008 ◽  
Vol 154 (2) ◽  
pp. 484-490 ◽  
Author(s):  
Twishasri Das Gupta ◽  
Boudhayan Bandyopadhyay ◽  
Sujoy K. Das Gupta
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Dna Binding ◽  
Binding Activity ◽  
Dna Binding Activity

scholarly journals Targeting neuropilin-1 suppresses the stability of CD4+CD25+ regulatory T cells via the NF-κB signaling pathway in sepsis

2020 ◽  
Author(s):  
Yu-lei Gao ◽  
Chun-xue Wang ◽  
Zi-yi Wang ◽  
Wen-jie Li ◽  
Yan-cun Liu ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Signaling Pathway ◽  
Binding Activity ◽  
Dna Binding Activity ◽  
Sepsis Model ◽  
The Stability ◽  
The Impact ◽  
Tgf Β1

Neuropilin (Nrp)-1 contributes to maintain the stability of CD4+CD25+ regulatory T cells (Tregs). We investigated the impact of Nrp-1 on the stability of CD4+CD25+ Tregs, and the underlying signaling pathways, in a sepsis model. Splenic CD4+CD25+ Tregs were treated with anti-Nrp-1, or transfected to silence Nrp-1 and ikkβ, or administered with PDTC, followed by rSema3A in sepsis simulation. After creation of a sepsis model in mice, anti-Nrp-1 was administered. Expression of foxp3- TSDR, apoptosis rate, Foxp-3/CTLA-4/TGF-β1, IL-10 and TGF-β1, and NF-κB signaling activity of CD4+CD25+ Tregs were determined. Sepsis simulation with or without rSema3A increased the stability of CD4+CD25+ Tregs, including an increase in the expression of Foxp-3/CTLA-4/TGF-β1, decrease in apoptosis and methylation of foxp3- TSDR, increase in the secretion of TGF-β1 and IL-10, and increase in the immunosuppressive effect on CD4+T lymphocytes. silencing of Nrp-1 or anti-Nrp-1 treatment interdicted LPS stimulation with or without a rSema3A-mediated effect. Sepsis simulation increased the DNA-binding activity of NF-κB, as well as the p-ikkβ/ikkβ and p-P65/P65 ratios in vitro and vivo. Silencing of ikkβ expression or PDTC treatment suppressed the stability of CD4+CD25+ Tregs in LPS-induced sepsis. Weakening Nrp-1 reduced the stability of CD4+CD25+ Tregs by regulating the NF-κB signaling pathway, and could be a new target for immunoregulation in sepsis.

scholarly journals Rapid activation of the STAT3 transcription factor by granulocyte colony-stimulating factor

Blood ◽  
1994 ◽  
Vol 84 (6) ◽  
pp. 1760-1764 ◽  
Author(s):  
SS Tian ◽  
P Lamb ◽  
HM Seidel ◽  
RB Stein ◽  
J Rosen
Keyword(s):  
Dna Binding ◽  
Tyrosine Phosphorylation ◽  
Tyrosine Kinases ◽  
Signal Transduction Pathway ◽  
Binding Activity ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Dna Binding Activity ◽  
Dna Binding Complexes ◽  
Stimulating Factor

Abstract Granulocyte colony-stimulating factor (G-CSF) is a glycoprotein that stimulates proliferation and differentiation of progenitor cells of neutrophils by signaling through its receptor (G-CSFR). Although the G- CSFR belongs to the cytokine receptor superfamily, which lacks an intracellular kinase domain, G-CSF-induced tyrosine phosphorylation of cellular proteins is critical for its biologic activities. We report here that JAK1 and JAK2 tyrosine kinases are tyrosine phosphorylated in response to G-CSF induction. We also demonstrate that the DNA-binding protein STAT3 (also called the acute-phase response factor [APRF], activated by interleukin-6) is an early target of G-CSF-induced tyrosine phosphorylation. G-CSF induces two DNA-binding complexes; the major complex contains tyrosine phosphorylated STAT3 protein and the minor complex appears to be a heterodimer of the STAT1 (previously p91, a component of DNA-binding complexes activated by interferons) and STAT3 proteins. Antiphosphotyrosine antibody interferes with the DNA binding activity of activated STAT3, indicating that tyrosine phosphorylation of STAT3 is important for the DNA binding activity. These results identify a signal transduction pathway activated in response to G-CSF and provide a mechanism for the rapid modulation of gene expression by G-CSF.

scholarly journals Regulation of Transcription Factors and Repression of Sp1 by Prolactin Signaling Through the Short Isoform of Its Cognate Receptor

Endocrinology ◽  
2009 ◽  
Vol 150 (7) ◽  
pp. 3327-3335 ◽  
Author(s):  
Y. Sangeeta Devi ◽  
Aurora Shehu ◽  
Carlos Stocco ◽  
Julia Halperin ◽  
Jamie Le ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Signaling Pathway ◽  
Short Form ◽  
Binding Activity ◽  
In Vivo Model ◽  
Regulation Of Transcription ◽  
Signaling Mechanism ◽  
Dna Binding Activity ◽  
And Function

Prolactin (PRL) affects the development and function of the reproductive system by binding to two types of receptors, which differ by the size of their intracellular domain in rodents. Whereas the signaling pathway through the long form of the receptor (PRL-RL) is well characterized, signaling through the short form (PRL-RS) remains obscure. In this investigation, we examined transcription factors regulated by PRL in the ovary and decidua of mice expressing only PRL-RS in a PRL receptor null background. These mice provide a powerful in vivo model to study the selective signaling mechanism of PRL through PRL-RS independent of PRL-RL. We also examined the regulation of transcription factors in ovarian and uterine cell lines stably transfected with PRL-RS or PRL-RL. We focused our investigation on transcription factors similarly regulated in both these tissues and clearly established that signaling through PRL-RS does not activate the JaK/Stat in vivo but leads to severe down-regulation of Sp1 expression, DNA binding activity, and nuclear localization, events that appear to involve the calmodulin-dependent protein kinase pathway. Our in vivo and in culture data demonstrate that the PRL-RS activates a signaling pathway distinct from that of the PRL-RL.

scholarly journals The Adenovirus L4 33-Kilodalton Protein Binds to Intragenic Sequences of the Major Late Promoter Required for Late Phase-Specific Stimulation of Transcription

2006 ◽  
Vol 81 (3) ◽  
pp. 1327-1338 ◽  
Author(s):  
Humayra Ali ◽  
Gary LeRoy ◽  
Gemma Bridge ◽  
S. J. Flint
Keyword(s):  
Dna Binding ◽  
Late Phase ◽  
Promoter Sequence ◽  
Specific Protein ◽  
Binding Activity ◽  
Progeny Virus ◽  
Dna Binding Activity ◽  
Protein Dimer ◽  
Specific Stimulation ◽  
Stimulation Of

ABSTRACT The adenovirus late IVa2 protein is required for maximally efficient transcription from the viral major late (ML) promoter, and hence, the synthesis of the majority of viral late proteins. This protein is a sequence-specific DNA-binding protein that also promotes the assembly of progeny virus particles. Previous studies have established that a IVa2 protein dimer (DEF-B) binds specifically to an intragenic ML promoter sequence necessary for late phase-specific stimulation of ML transcription. However, activation of transcription from the ML promoter correlates with binding of at least one additional infected-cell-specific protein, termed DEF-A, to the promoter. Using an assay for the DNA-binding activity of DEF-A, we identified the unknown protein by using conventional purification methods, purification of FLAG-tagged IVa2-protein-containing complexes, and transient synthesis of viral late proteins. The results of these experiments established that the viral L4 33-kDa protein is the only component of DEF-A: the IVa2 and L4 33-kDa proteins are necessary and sufficient for formation of all previously described complexes in the intragenic control region of the ML promoter. Furthermore, the L4 33-kDa protein binds to the promoter with the specificity characteristic of DEF-A and stimulates transcription from the ML promoter in transient-expression assays.

scholarly journals The role of GH receptor tyrosine phosphorylation in Stat5 activation

1997 ◽  
Vol 18 (3) ◽  
pp. 213-221 ◽  
Author(s):  
J A Hansen ◽  
L H Hansen ◽  
X Wang ◽  
J J Kopchick ◽  
F Gouilleux ◽  
...  
Keyword(s):  
Dna Binding ◽  
Tyrosine Phosphorylation ◽  
Transcriptional Response ◽  
Binding Activity ◽  
Gh Receptor ◽  
Dna Binding Activity ◽  
Phosphorylated Peptides ◽  
Receptor Mutant ◽  
Rapid Activation ◽  
Gh Receptors

ABSTRACT Stimulation of GH receptors leads to rapid activation of Jak2 kinase and subsequent tyrosine phosphorylation of the GH receptor. Three specific tyrosines located in the C-terminal domain of the GH receptor have been identified as being involved in GH-stimulated transcription of the Spi 2·1 promoter. Mutated GH receptors lacking all but one of these three tyrosines are able to mediate a transcriptional response when transiently transfected into CHO cells together with a Spi 2·1 promoter/luciferase construct. Similarly, these GH receptors were found to be able to mediate activation of Stat5 DNA-binding activity, whereas the GH receptor mutant lacking all intracellular tyrosines was not. Synthetic tyrosine phosphorylated peptides corresponding to the GH receptor sequence around the three tyrosines inhibited Stat5 DNA-binding activity while their non-phosphorylated counterparts were ineffective. Tyrosine phosphorylated GST-GH receptor fusion proteins specifically bound to Stat5 in extracts from COS 7 cells transfected with Stat5 cDNA. This binding could be inhibited by tyrosine phosphorylated peptides derived from the GH receptor. This study thus demonstrated that specific GH receptor tyrosine residues, in their phosphorylated state, are involved in transcriptional signaling by directly interacting with Stat5.

High glucose-induced NF-κB activation occurs via tyrosine phosphorylation of IκBα in human glomerular endothelial cells: involvement of Syk tyrosine kinase

2008 ◽  
Vol 294 (5) ◽  
pp. F1065-F1075 ◽  
Author(s):  
Won Seok Yang ◽  
Jang Won Seo ◽  
Nam Jeong Han ◽  
Jung Choi ◽  
Ki-Up Lee ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Tyrosine Phosphorylation ◽  
High Glucose ◽  
Nuclear Translocation ◽  
Binding Activity ◽  
Serine Phosphorylation ◽  
Dna Binding Activity ◽  
Kinase C ◽  
Human Glomerular Endothelial Cells

Activation of nuclear factor-κB (NF-κB) occurs by dissociation from IκB after serine or tyrosine phosphorylation of IκBα, but the way of NF-κB activation by high glucose has not been defined. High glucose is known to activate NF-κB via protein kinase C and reactive oxygen species (ROS). In this study, we investigated how high glucose activates NF-κB for CC chemokine ligand 2 production in cultured human glomerular endothelial cells. High glucose increased nuclear translocation of p65 and also increased NF-κB DNA binding activity. High glucose-induced NF-κB activation occurred without degradation of IκBα. In agreement with this, there was no increase in serine phosphorylation of IκBα, while tyrosine phosphorylation of IκBα was increased by high glucose. High glucose increased the generation of ROS, whereas both α-lipoic acid and N-acetylcysteine scavenged the ROS and decreased high glucose-induced tyrosine phosphorylation of IκBα, nuclear translocation of p65, and NF-κB DNA binding activity. Protein kinase C pseudosubstrate inhibited high glucose-induced ROS production, tyrosine phosphorylation of IκBα, and nuclear translocation of p65. Both BAY 61-3606, a specific inhibitor of Syk protein-tyrosine kinase, and small interfering RNA directed against Syk inhibited high glucose-induced tyrosine phosphorylation of IκBα as well as p65 nuclear translocation. High glucose increased tyrosine phosphorylation of Syk, while it was inhibited by α-lipoic acid and protein kinase C pseudosubstrate. In summary, high glucose-induced NF-κB activation occurred not by serine phosphorylation of IκBα. Our data suggest that ROS-mediated tyrosine phosphorylation of IκBα is the mechanism for high glucose-induced NF-κB activation, and Syk may play a role in tyrosine phosphorylation of IκBα.

scholarly journals Erythroblast Transformation by the Friend Spleen Focus-Forming Virus Is Associated with a Block in Erythropoietin-Induced STAT1 Phosphorylation and DNA Binding and Correlates with High Expression of the Hematopoietic Phosphatase SHP-1

2006 ◽  
Vol 80 (12) ◽  
pp. 5678-5685 ◽  
Author(s):  
Kazuo Nishigaki ◽  
Charlotte Hanson ◽  
Takashi Ohashi ◽  
Angelo Spadaccini ◽  
Sandra Ruscetti
Keyword(s):  
Dna Binding ◽  
Tyrosine Phosphorylation ◽  
Short Form ◽  
Leukemia Virus ◽  
Binding Activity ◽  
Erythropoietin Receptor ◽  
Erythroid Cell ◽  
Dna Binding Activity ◽  
Erythroid Hyperplasia ◽  
Murine Erythroleukemia

ABSTRACT Infection of mice with Friend spleen focus-forming virus (SFFV) results in a multistage erythroleukemia. In the first stage, the SFFV envelope glycoprotein interacts with the erythropoietin receptor and a short form of the receptor tyrosine kinase sf-Stk, resulting in constitutive activation of signal transducing molecules and the development of erythropoietin (Epo)-independent erythroid hyperplasia and polycythemia. The second stage results from the outgrowth of a rare virus-infected erythroid cell that expresses nonphysiological levels of the myeloid transcription factor PU.1. These cells exhibit a differentiation block and can be grown as murine erythroleukemia (MEL) cell lines. In this study, we examined SFFV MEL cells to determine whether their transformed phenotype was associated with a block in the activation of any Epo signal-transducing molecules. Our studies indicate that Epo- or SFFV-induced activation of STAT1/3 DNA binding activity is blocked in SFFV MEL cells. The block is at the level of tyrosine phosphorylation of STAT1, although Jak2 phosphorylation is not blocked in these cells. In contrast to Epo, alpha interferon can induce STAT1 phosphorylation and DNA binding in SFFV MEL cells. The SFFV-transformed cells were shown to express elevated levels of the hematopoietic phosphatase SHP-1, and treatment of the cells with a phosphatase inhibitor restored STAT1 tyrosine phosphorylation. MEL cells derived from Friend murine leukemia virus (MuLV) or ME26 MuLV-infected mice, which do not express PU.1, express lower levels of SHP-1 and are not blocked in STAT1/3 DNA-binding activity. Our studies suggest that SFFV-infected erythroid cells become transformed when differentiation signals activated by STAT1/3 are blocked due to high SHP-1 levels induced by inappropriate expression of the PU.1 protein.

Sign in / Sign up

Export Citation Format

Share Document