CoChat
Sign Up
Cited by 255Cytokine Signaling Pathways and InteractionsNF-κB Signaling PathwaysNitric Oxide and Endothelin Effects

Signal transducers and activators of transcription 3 (STAT3) inhibits transcription of the inducible nitric oxide synthase gene by interacting with nuclear factor κB

Open access
YU, Zhiyuan, ZHANG, Wenzheng, KONE, Bruce C.·2002·Biochemical Journal
DOI 10.1042/bj20020588PMC PMC1222853
Open this paper in CoChat — free accountOpen PDF

Abstract

Prolific generation of NO by inducible nitric oxide synthase (iNOS) can cause unintended injury to host cells during glomerulonephritis and other inflammatory diseases. While much is known about the mechanisms of iNOS induction, few transcriptional repressors have been found. We explored the role of signal transducers and activators of transcription 3 (STAT3) proteins in interleukin (IL)-1β- and lipopolysaccharide (LPS)+interferon (IFN)-γ-mediated iNOS induction in murine mesangial cells. Both stimuli induced rapid phosphorylation of STAT3 and sequence-specific STAT3 DNA-binding activity. Supershift assays with a STAT3 element probe demonstrated that nuclear factor κB (NF-κB) p65 and p50 complexed with STAT3 in the DNA—protein complex. The direct interaction of STAT3 and NF-κB p65 was verified in vivo by co-immunoprecipitation and in vitro by pull-down assays with glutathione S-transferase-NF-κB p65 fusion protein and in vitro-translated STAT3α. Overexpression of STAT3 dramatically inhibited IL-1β- or LPS+IFN-γ-mediated induction of iNOS promoter-luciferase constructs that contained the wild-type iNOS promoter or ones harbouring mutated STAT-binding elements. In tests of indirect inhibitory effects of STAT3, overexpression of STAT3 dramatically inhibited the activity of an NF-κB-dependent promoter devoid of STAT-binding elements without affecting NF-κB DNA-binding activity. Thus STAT3, via direct interactions with NF-κB p65, serves as a dominant-negative inhibitor of NF-κB activity to suppress indirectly cytokine induction of the iNOS promoter in mesangial cells. These results provide a new model for the termination of NO production by activated iNOS following exposure to pro-inflammatory stimuli.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1042/bj20020588

Cites

34 of 34 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The suggested mechanisms for the STAT3-NF-κB crosstalk are often contradictory and a consensus has not been reached.

    “Thus, the suggested mechanisms for the STAT3-NF-κB crosstalk are often contradictory and a consensus has not been reached.”

    From Synergistic gene expression during the acute phase response is characterized by transcription factor assisted loading (2017) · cites this paper as [19]

    The introduction says relatively little is known about how transcription-factor interactions regulate iNOS, and the discussion says the domains mediating the STAT3–NF-κB interaction remain unidentified (page numbers unavailable). These passages support uncertainty about the mechanism, but the paper does not say proposed mechanisms are often contradictory or that the field lacks a consensus. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

  • The crosstalk between STAT3 and NF-κB is an active field of research with studies showing contradictory outcomes of concomitant activation of the two TFs.

    “The crosstalk between STAT3 and NF-κB is an active field of research with studies showing contradictory outcomes of concomitant activation of the two TFs.”

    From Synergistic gene expression during the acute phase response is characterized by transcription factor assisted loading (2017) · cites this paper as [19]

    The introduction (page unavailable) describes cooperative and antagonistic interactions involving STAT proteins and NF-κB, and the paper reports that STAT3 antagonizes NF-κB signaling in activated mesangial cells. It does not establish that studies found contradictory outcomes specifically for concomitant STAT3 and NF-κB activation; its broader examples include other STAT proteins. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Some studies suggest cooperation between STAT3 and NF-κB, while others show antagonism.

    “Some suggest cooperation between them, while others show antagonism2, 16–21.”

    From Synergistic gene expression during the acute phase response is characterized by transcription factor assisted loading (2017) · cites this paper as [19]

    The introductory passage (page unavailable) says STAT proteins and NF-κB can act cooperatively, but does not establish cooperation specifically between STAT3 and NF-κB. The paper does show that STAT3 antagonizes NF-κB-dependent transcription in activated mesangial cells, supporting the antagonism part of the claim. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

1 of the 35 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

Related

Authors
YU, Z., ZHANG, W., & KONE, B. C.
Affiliations
The University of Texas Health Science Center at Houston (US)
ORCID
Venue
Biochemical Journal
Publisher
Portland Press Ltd.
Published
2002-10-01
Volume
367
Issue
1
Pages
97-105
ISSN
  • 0264-6021 (ISSN-L)
  • 1470-8728
DOI
10.1042/bj20020588
PMC
PMC1222853
OpenAlex
W1983667136
Cited by
255
References
35
Citations by year
2026: 2 · 2025: 2 · 2024: 4 · 2023: 7 · 2022: 8 · 2021: 10 · 2020: 7 · 2019: 6 · 2018: 8 · 2017: 20 · 2016: 13 · 2015: 13 · 2014: 19 · 2013: 16 · 2012: 14
FWCI
4.29
Type
journal article
Language
en
Open access
Locations
  • Biochemical Journal (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (5r01dk050745-05)
  • National Institute of General Medical Sciences (P50GM038529, P50 GM 38529)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK 50745)
Topics
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
Keywords
STAT3, inducible nitric oxide synthase, NF-κB p65, mesangial cells, IL-1β, lipopolysaccharide, interferon-gamma, nitric oxide production, glomerulonephritis, transcriptional repressor, dominant negative inhibition
MeSH terms
Animals, Cell Nucleus, Cells, Cultured, DNA, DNA-Binding Proteins, Electrophoresis, Polyacrylamide Gel, Genes, Dominant, Glutathione Transferase, Inflammation, Interleukin-1, Nitric Oxide, Nitrites, Phosphorylation, Plasmids, Precipitin Tests, Promoter Regions, Genetic, Protein Binding, Recombinant Fusion Proteins, Transcription, Genetic, Transfection, Protein Biosynthesis, Blotting, Western, Trans-Activators, Cytokines, Mutagenesis, Site-Directed, NF-kappa B, Nitric Oxide Synthase, Protein Isoforms, STAT3 Transcription Factor, Mice, Transcription Factor RelA, NF-kappa B p50 Subunit, Nitric Oxide Synthase Type II

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review