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J Allergy Clin Immunol. 2016 Jul;138(1):187-199. doi: 10.1016/j.jaci.2015.11.024. Epub 2016 Mar 2.

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

Author information

1
Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
2
Clinical Research Directorate/CMRP, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Md.
3
Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md.
4
Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
5
Section of Infectious Diseases, Department of Medicine, Baylor College of Medicine, Houston, Md.
6
Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md. Electronic address: jdmilner@niaid.nih.gov.

Erratum in

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.

KEYWORDS:

Allergy; autosomal dominant hyper-IgE syndrome; immunology; innate immunity; signal transducer and activator of transcription 3

PMID:
26948077
PMCID:
PMC4931983
DOI:
10.1016/j.jaci.2015.11.024
[Indexed for MEDLINE]
Free PMC Article

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