Faculty Opinions recommendation of Inhibition of JNK activation through NF-kappaB target genes.

IkappaB alpha retains the transcription factor NF-kappaB in the cytoplasm, thus inhibiting its function. Various stimuli inactivate IkappaB alpha by triggering phosphorylation of the N-terminal residues Ser32 and Ser36. Phosphorylation of both serines is demonstrated directly by phosphopeptide mapping utilizing calpain protease, which cuts approximately 60 residues from the N terminus, and by analysis of mutants lacking one or both serine residues. Phosphorylation is followed by rapid proteolysis, and the liberated NF-kappaB translocates to the nucleus, where it activates transcription of its target genes. Transfer of the N-terminal domain of IkappaB alpha to the ankyrin domain of the related oncoprotein Bcl-3 or to the unrelated protein glutathione S-transferase confers signal-induced phosphorylation on the resulting chimeric proteins. If the C-terminal domain of IkappaB alpha is transferred as well, the resulting chimeras exhibit both signal-induced phosphorylation and rapid proteolysis. Thus, the signal response of IkappaB alpha is controlled by transferable N-terminal and C-terminal domains.

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The Signal Pathways of Immune Inflammation Mediated by the Tlr3/Nf-Kappab and Activator Protein-1 in Cells Infected with Influenza A Virus Antagonized by Baicalin

Advanced Materials Research ◽

10.4028/www.scientific.net/amr.345.201 ◽

2011 ◽

Vol 345 ◽

pp. 201-209

Author(s):

Chun Jing Zhang ◽

Hai Tao Yu

Keyword(s):

Influenza A Virus ◽

Influenza A ◽

Target Genes ◽

Expression Level ◽

Signal Pathways ◽

Significant Activity ◽

Influenza A Viruses ◽

Downstream Target ◽

Nf Kappab ◽

In Cells

Baicalin has better anti-inflammatory function, antioxidant function and antiviral activity, but the mechanism of the antiinfluenza viral activity of baicalin has not been revealed.Toll-like Receptor 3 and the signal pathways mediated by TLR3 were affected and controlled by the infections with influenza A virus. We report here the significant activity and part mechanism of baicalin against H3N2 influenza A viruses. Baicalin could well protect the damages of cells caused by influenza A virus, it also could effectively inhibit the production of CPE in cells caused by influenza A virus and the inhibition of cells growth. The mechanism of antiinfluenza virus infection of baicalin may be related with the following aspects: to decrease the transcriptional activity of the oxidative stress sensitive transcription factor NF-kappaB and AP-1 by moderately decrease the higher expression level of TLR3 mRNA and the higher expression level of protein; and to further inhibit the mRNA expression of the downstream target genes IL-1β, IL-8, RANTES and IFN-β thereby alleviate the inflammatory injuries and restore the stability and balance of immune function in vivro.

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Characterization of a mutant cell line that does not activate NF-kappaB in response to multiple stimuli.

Molecular and Cellular Biology ◽

10.1128/mcb.17.3.1441 ◽

1997 ◽

Vol 17 (3) ◽

pp. 1441-1449 ◽

Cited By ~ 66

Author(s):

G Courtois ◽

S T Whiteside ◽

C H Sibley ◽

A Israel

Keyword(s):

Cell Line ◽

Target Genes ◽

Leukemia Virus ◽

Mutant Cell ◽

Interleukin 1 ◽

Redox Status ◽

Pyrrolidine Dithiocarbamate ◽

Cell Leukemia Virus Type ◽

Human T Cell ◽

Nf Kappab

Numerous genes required during the immune or inflammation response as well as the adhesion process are regulated by nuclear factor kappaB (NF-kappaB). Associated with its inhibitor, I kappaB, NF-kappaB resides as an inactive form in the cytoplasm. Upon stimulation by various agents, I kappaB is proteolyzed and NF-kappaB translocates to the nucleus, where it activates its target genes. The transduction pathways that lead to I kappaB inactivation remain poorly understood. In this study, we have characterized a cellular mutant, the 70/Z3-derived 1.3E2 murine pre-B cell line, that does not activate NF-kappaB in response to several stimuli. We demonstrate that upon stimulation by lipopolysaccharide, Taxol, phorbol myristate acetate, interleukin-1, or double-stranded RNA, I kappaB alpha is not degraded, as a result of an absence of induced phosphorylation on serines 32 and 36. Neither a mutation in I kappaB alpha nor a mutation in p50 or relA, the two major subunits of NF-kappaB in this cell line, accounts for this phosphorylation defect. As well as culminating in the inducible phosphorylation of I kappaB alpha on serines 32 and 36, all the stimuli that are inactive on 1.3E2 cells exhibit a sensitivity to the antioxidant pyrrolidine dithiocarbamate (PDTC). In contrast, stimuli such as hyperosmotic shock or phosphatase inhibitors, which use PDTC-insensitive pathways, induce I kappaB alpha degradation in 1.3E2. Analysis of the redox status of 1.3E2 does not reveal any difference from wild-type 70Z/3. We also report that the human T-cell leukemia virus type 1 (HTLV-1)-derived Tax trans-activator induces NF-kappaB activity in 1.3E2, suggesting that this viral protein does not operate via the defective pathway. Finally, we show that two other I kappaB molecules, I kappaB beta and the recently identified I kappaB epsilon, are not degraded in the 1.3E2 cell line following stimulation. Our results demonstrate that 1.3E2 is a cellular transduction mutant exhibiting a defect in a step that is required by several different stimuli to activate NF-kappaB. In addition, this analysis suggests a common step in the signaling pathways that trigger I kappaB alpha, I kappaB beta, and I kappaB epsilon degradation.

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FOXO mediates organismal hypoxia tolerance by regulating NF-κB in Drosophila

10.1101/679605 ◽

2019 ◽

Author(s):

Elizabeth C Barretto ◽

Danielle M Polan ◽

Amy N Beever-Potts ◽

Byoungchun Lee ◽

Savraj S Grewal

Keyword(s):

Transcription Factor ◽

Target Genes ◽

Hypoxia Inducible Factor ◽

Innate Immune ◽

Hypoxia Tolerance ◽

Dependent Manner ◽

Low Oxygen ◽

Hypoxia Exposure ◽

Pathological Conditions ◽

Nf Kappab

ABSTRACTExposure of tissues and organs to low oxygen (hypoxia) occurs in both physiological and pathological conditions in animals. Under these conditions, organisms have to adapt their physiology to ensure proper functioning and survival. Here we define a role for the transcription factor FOXO as a mediator of hypoxia tolerance in Drosophila. We find that upon hypoxia exposure, FOXO transcriptional activity is rapidly induced in both larvae and adults. Moreover, we see that foxo mutant animals show misregulated glucose metabolism in low oxygen and subsequently exhibit reduced hypoxia survival. We identify the innate immune transcription factor, NF-KappaB/Relish, as a key FOXO target in the control of hypoxia tolerance. We find that expression of Relish and its target genes are increase in a FOXO-dependent manner in hypoxia, and that relish mutant animals show reduced survival in hypoxia. Together, these data indicate that FOXO is a hypoxia inducible factor that mediates tolerance to low oxygen by inducing immune-like responses.

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Thiopental Inhibits the Activation of Nuclear Factor κB

Anesthesiology ◽

10.1097/00000542-200205000-00025 ◽

2002 ◽

Vol 96 (5) ◽

pp. 1202-1213 ◽

Cited By ~ 42

Author(s):

Torsten Loop ◽

Zhiheng Liu ◽

Matjaz Humar ◽

Alexander Hoetzel ◽

Albert Benzing ◽

...

Keyword(s):

Transcription Factor ◽

Reporter Gene ◽

T Cell Activation ◽

Cell Activation ◽

Target Genes ◽

Interleukin 2 ◽

Gene Activity ◽

Jurkat Cells ◽

Reporter Gene Activity ◽

Nf Kappab

Background Thiopental is frequently used for the treatment of intracranial hypertension after severe head injury. Its long-term administration increases the incidence of nosocomial infections, which contributes to the high mortality rate of these patients. However, the mechanism of its immunosuppressing effect remains unknown. Methods The effect of thiopental (200-1000 microg/ml) on the activation of the nuclear transcription factor kappaB (NF-kappaB; electrophoretic mobility shift assays), on NF-kappaB-driven reporter gene activity (transient transfection assays), on the expression of NF-kappaB target genes (enzyme-linked immunoassays), on T-cell activation (flow cytometric analyses of CD69 expression), and on the content of the NF-kappaB inhibitor IkappaB-alpha (Western blotting) was studied in human T lymphocytes in vitro. Results Thiopental inhibited the activation of the transcription factor NF-kappaB but did not alter the activity of the cyclic adenosine monophosphate response element binding protein. Other barbiturates (methohexital), anesthetics (etomidate, propofol, ketamine), or opioids (fentanyl, morphine) did not affect NF-kappaB activation. Thiopental-mediated suppression of NF-kappaB could be observed in Jurkat cells and in primary CD3+ lymphocytes from healthy volunteers, was time- and concentration-dependent, occurred at concentrations that are clinically achieved, and persisted for hours after the incubation. It was associated with an inhibition of NF-kappaB-driven reporter gene activity, of the expression of interleukin-2, -6, and -8, and interferon gamma, and of the activation of CD3+ lymphocytes. Suppression of NF-kappaB appeared to involve reduced degradation of IkappaB-alpha. Conclusion The results demonstrate that thiopental inhibits the activation of NF-kappaB and may thus provide a molecular mechanism for some of the immunosuppressing effects associated with thiopental therapy.

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