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Cited by 247NF-κB Signaling PathwaysCell Adhesion Molecules ResearchNitric Oxide and Endothelin Effects

A20 Blocks Endothelial Cell Activation through a NF-κB-dependent Mechanism

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Cooper, Jeffrey T., Stroka, Deborah M., Brostjan, Christine, Palmetshofer, Alois, Bach, Fritz H., Ferran, Christiane·1996·Journal of Biological Chemistry
DOI 10.1074/jbc.271.30.18068
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Abstract

The A20 gene product is a novel zinc finger protein originally described as a tumor necrosis factor alpha (TNF)-inducible early response gene in human umbilical vein endothelial cells (HUVEC). Its described function is to block TNF-induced apoptosis in fibroblasts and B lymphocytes, but more recently it has also been shown to play a role in lymphoid cell maturation. The mechanism of action of A20 is unknown. The aim of our study was to assess the effect of A20 upon endothelial cell activation. By transfecting bovine aortic endothelial cells (BAEC) with A20 as well as reporter constructs consisting of the promoters of genes known to be up-regulated during endothelial cell activation, i.e. E-selectin, interleukin (IL)-8, tissue factor (TF), and inhibitor of nuclear factor kappaBalpha (IkappaBalpha), we demonstrate that A20 expression inhibits gene up-regulation associated with TNF, lipopolysaccharide (LPS), phorbol 12-myristate 13-acetate (PMA), and hydrogen peroxide (H2O2)-induced endothelial cell (EC) activation. The mechanism of action of A20 is in part, or totally, due to the blockade of nuclear factor kappaB (NF-kappaB), as shown by its ability to suppress the activity of a NF-kappaB reporter. This effect is specific, as A20 does not block a noninducible, constitutively expressed reporter, Rous sarcoma virus-luciferase (RSV-LUC); nor does it block the c-Tat-inducible, NF-kappaB-independent reporter, human immunodeficiency virus-chloramphenicol acetyltransferase (HIV-CAT). How A20 blocks NF-kappaB is unclear, although we demonstrate that it does not affect p65 (RelA)-mediated gene transactivation. The inhibition of endothelial cell activation by A20 is a novel function for A20.

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  • A20 exerts multiple hepatoprotective functions through combined anti-inflammatory, anti-apoptotic, and pro-proliferative effects in hepatocytes.

    “We previously demonstrated that A20/tnfaip3, a key element of the cellular response to injury and inflammation (12, 13), exerts multiple hepatoprotective functions through combined anti-inflammatory, anti-apoptotic, and pro-proliferative effects in hepatocytes (14–16).”

    From A20 promotes liver regeneration by decreasing SOCS3 expression to enhance IL-6/STAT3 proliferative signals (2013) · cites this paper as [12]

    The paper reports that A20 inhibits NF-κB-dependent endothelial cell activation and discusses its protection against apoptosis (Discussion; page not supplied). It does not establish anti-inflammatory, anti-apoptotic, or pro-proliferative effects in hepatocytes, so the hepatoprotective and proliferation parts of the claim are unsupported by this source. (LLM, conf=0.88)

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Research works printed but not linked: 2

  1. Crossman, D. C., Carr, D. P., Tuddenham, E. G. D., Pearson, J. D., and McVey, J. H. (1990) J. Biol. Chem. 265, 9782-9787
  2. Winer, B. J. (1971) Statistical Principle in Experimental Design, 2nd Ed., McGraw-Hill, New York

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Authors
Cooper, J. T., Stroka, D. M., Brostjan, C., Palmetshofer, A., Bach, F. H., & Ferran, C.
Affiliations
Harvard University (US)
Corresponding author
Ferran, Christiane
ORCID
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
1996-07
Volume
271
Issue
30
Pages
18068-18073
ISSN
0021-9258 (ISSN-L)
DOI
10.1074/jbc.271.30.18068
OpenAlex
W2031585752
Cited by
247
References
37
Citations by year
2026: 3 · 2025: 1 · 2024: 5 · 2023: 3 · 2022: 1 · 2021: 3 · 2020: 4 · 2019: 3 · 2018: 3 · 2017: 5 · 2016: 6 · 2015: 7 · 2014: 12 · 2013: 8 · 2012: 11
FWCI
7.33
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
  • Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
Keywords
A20, endothelial activation, NF-κB, zinc finger proteins, TNF signaling, E-selectin, interleukin-8, tissue factor, IκBα, lipopolysaccharide, phorbol myristate acetate, hydrogen peroxide, RelA/p65, transcriptional repression
MeSH terms
Tumor Necrosis Factor alpha-Induced Protein 3, Animals, Aorta, Cattle, Cell Differentiation, DNA-Binding Proteins, Endothelium, Vascular, Humans, Nuclear Proteins, Proteins, Recombinant Proteins, Transfection, Tumor Necrosis Factor-alpha, Signal Transduction, NF-kappa B, Zinc Fingers, Apoptosis, Genes, Reporter, Intracellular Signaling Peptides and Proteins

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