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Cited by 64Mast cells and histamineImmunodeficiency and Autoimmune DisordersCytokine Signaling Pathways and Interactions

Diminution of signal transducer and activator of transcription 3 signaling inhibits vascular permeability and anaphylaxis

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Hox, Valerie, O'Connell, Michael P., Lyons, Jonathan J., Sackstein, Paul, Dimaggio, Thomas, Jones, Nina, Nelson, Celeste, Boehm, Manfred +6 more·2016·Journal of Allergy and Clinical Immunology
DOI 10.1016/j.jaci.2015.11.024PMC PMC4931983
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Abstract

Background During IgE-mediated immediate hypersensitivity reactions, vascular endothelial cells permeabilize in response to mast cell mediators. We have demonstrated previously that patients and mice with signal transducer and activator of transcription 3 (STAT3) mutations (autosomal dominant hyper-IgE syndrome [AD-HIES]) are partially protected from anaphylaxis. Objectives We sought to study the mechanism by which STAT3 contributes to anaphylaxis and determine whether small-molecule inhibition of STAT3 can prevent anaphylaxis. Methods Using unaffected and STAT3-inhibited or genetic loss-of-function samples, we performed histamine skin prick tests, investigated the contribution of STAT3 to animal models of anaphylaxis, and measured endothelial cell permeability, gene and protein expression, and histamine receptor-mediated signaling. Results Although mouse mast cell degranulation was minimally affected by STAT3 blockade, mast cell mediator-induced anaphylaxis was blunted in Stat3 mutant mice with AD-HIES and in wild-type mice subjected to small-molecule STAT3 inhibition. Histamine skin prick test responses were diminished in patients with AD-HIES. Human umbilical vein endothelial cells derived from patients with AD-HIES or treated with a STAT3 inhibitor did not signal properly through Src or cause appropriate dissolution of the adherens junctions made up of the proteins vascular endothelial-cadherin and β-catenin. Furthermore, we found that diminished STAT3 target microRNA17-92 expression in human umbilical vein endothelial cells from patients with AD-HIES is associated with increased phosphatase and tensin homolog (PTEN) expression, which inhibits Src, and increased E2F transcription factor 1 expression, which regulates β-catenin cellular dynamics. Conclusions These data demonstrate that STAT3-dependent transcriptional activity regulates critical components for the architecture and functional dynamics of endothelial junctions, thus permitting vascular permeability.

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  • Studies in mut-Stat3 mice bearing two copies of the V463del STAT3 mutation demonstrated defective mast cell degranulation and reduced endothelial cell permeability.

    “Studies in the mut-Stat3 bearing two copies of the V463del STAT3 mutation frequently found in Job’s syndrome patients demonstrated both defective mast cell degranulation and reduced endothelial cell permeability”

    From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Hox et al., 2016

    The Results section reports reduced anaphylaxis in Stat3-mutant mice, and the Conclusions attribute reduced vascular permeability to impaired STAT3 signaling. But the Results explicitly say the mutant mice showed no significant difference in histamine release after challenge, contrary to the claim that their mast cell degranulation was defective. The cited passages do not specify the V463del genotype (page numbers unavailable). (LLM, conf=0.90)

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  • STAT3-dependent transcriptional activity within endothelial cells regulating microRNA17-92, PTEN, Src, E2F, and β-catenin is a more important contributor to reduced endothelial cell permeability and anaphylaxis protection in Job's syndrome patients.

    “the STAT3-dependent transcriptional activity within endothelial cells that regulates critical components involved in the architecture and functional dynamics of endothelial junctions, i.e., microRNA17-92, PTEN, Src, E2F, and β-catenin, is a more important contributor to reduced endothelial cell permeability and anaphylaxis protection in these patients”

    From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Hox et al., 2016

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  • In IgE/antigen anaphylaxis model and to histamine alone, hematocrit levels and local plasma transudate are significantly lower in TTI-101-treated mice compared with untreated mice.

    “Similar to findings in mut-Stat3 mice, Hox et al. (2016) found that hematocrit levels and local plasma transudate in response to the IgE/antigen anaphylaxis model and to histamine alone were significantly lower in TTI-101–treated mice compared with untreated mice.”

    From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Hox et al., 2016

    The Discussion reports significantly lower hematocrit levels and local plasma transudate after IgE/antigen or histamine exposure, but identifies the treated mice as receiving C188–9, not TTI-101. The Methods section on STAT3 inhibition likewise identifies C188–9 as the injected drug. Page numbers are unavailable in our copy. (LLM, conf=0.90)

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Cited by

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Authors
Hox, V., O'Connell, M. P., Lyons, J. J., Sackstein, P., Dimaggio, T., Jones, N., Nelson, C., Boehm, M., Holland, S. M., Freeman, A. F., Tweardy, D. J., Olivera, A., Metcalfe, D. D., & Milner, J. D.
Affiliations
  • National Institutes of Health (US)
  • Frederick National Laboratory for Cancer Research (US)
  • Baylor College of Medicine (US)
Corresponding author
Milner, Joshua D.
ORCID
Venue
Journal of Allergy and Clinical Immunology
Publisher
Elsevier BV
Published
2016-07
Volume
138
Issue
1
Pages
187-199
ISSN
0091-6749 (ISSN-L)
DOI
10.1016/j.jaci.2015.11.024
PMC
PMC4931983
OpenAlex
W2289721368
Cited by
64
References
2
Citations by year
2026: 1 · 2025: 4 · 2024: 6 · 2023: 5 · 2022: 9 · 2021: 9 · 2020: 11 · 2019: 3 · 2018: 13 · 2017: 3
FWCI
3.84
Type
journal article
Language
en
Update notices
erratum (2017-07-01)
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Journal of Allergy and Clinical Immunology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Digital Access to Libraries (Université catholique de Louvain (UCL), l'Université de Namur (UNamur) and the Université Saint-Louis (USL-B)) (submittedVersion, other-oa)
Funders
  • U.S. Department of Health and Human Services (HHSN261200800001E)
  • National Institutes of Health (#HHSN261200800001E, HHSN261200800001C)
  • National Cancer Institute (HHSN261200800001E))
  • National Institute of Allergy and Infectious Diseases (HHSN261200800001E, ZIAAI001098)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Mast cells and histamine
  • Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
Keywords
STAT3 signaling, anaphylaxis, vascular permeability, autosomal dominant hyper-IgE syndrome, endothelial adherens junctions, VE-cadherin, β-catenin, Src signaling, PTEN, E2F1, mast cell degranulation, IgE-mediated hypersensitivity, STAT3 inhibitor, histamine skin test
MeSH terms
Anaphylaxis, Animals, Capillary Permeability, Disease Models, Animal, Humans, Immunoglobulin E, Mast Cells, Mutation, Receptors, Histamine, Skin Tests, Signal Transduction, Cell Degranulation, Cytokines, Mice, Knockout, Inflammation Mediators, src-Family Kinases, Adherens Junctions, STAT3 Transcription Factor, beta Catenin, Mice, Human Umbilical Vein Endothelial Cells

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