title: Diminution of signal transducer and activator of transcription 3 signaling inhibits vascular permeability and anaphylaxis.
abstract: 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.
  
  
  
  We sought to study the mechanism by which STAT3 contributes to anaphylaxis and determine whether small-molecule inhibition of STAT3 can prevent anaphylaxis.
  
  
  
  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.
  
  
  
  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.
  
  
  
  These data demonstrate that STAT3-dependent transcriptional activity regulates critical components for the architecture and functional dynamics of endothelial junctions, thus permitting vascular permeability.
authors.affiliation: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Valerie
authors.initials: V
authors.lastname: Hox
authors.affiliation: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Michael P
authors.initials: MP
authors.lastname: O'Connell
authors.affiliation: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Lyons
authors.affiliation: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Paul
authors.initials: P
authors.lastname: Sackstein
authors.affiliation: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Thomas
authors.initials: T
authors.lastname: Dimaggio
authors.affiliation: Clinical Research Directorate/CMRP, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Md.
authors.forename: Nina
authors.initials: N
authors.lastname: Jones
authors.affiliation: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Celeste
authors.initials: C
authors.lastname: Nelson
authors.affiliation: Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md.
authors.forename: Manfred
authors.initials: M
authors.lastname: Boehm
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Holland
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Alexandra F
authors.initials: AF
authors.lastname: Freeman
authors.affiliation: Section of Infectious Diseases, Department of Medicine, Baylor College of Medicine, Houston, Md.
authors.forename: David J
authors.initials: DJ
authors.lastname: Tweardy
authors.affiliation: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Ana
authors.initials: A
authors.lastname: Olivera
authors.affiliation: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Dean D
authors.initials: DD
authors.lastname: Metcalfe
authors.affiliation: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md. Electronic address: jdmilner@niaid.nih.gov.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Milner
mesh_terms: D022005:Adherens Junctions / Q000378:metabolism; D000707:Anaphylaxis / Q000175:diagnosis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D015550:Cell Degranulation / Q000187:drug effects / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007073:Immunoglobulin E / Q000276:immunology; D018836:Inflammation Mediators / Q000378:metabolism; D008407:Mast Cells / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D011968:Receptors, Histamine / Q000276:immunology / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D012882:Skin Tests; D051176:beta Catenin / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D011968:Receptors, Histamine; D050796:STAT3 Transcription Factor; D051176:beta Catenin; D007073:Immunoglobulin E; D019061:src-Family Kinases
keywords: Allergy; autosomal dominant hyper-IgE syndrome; immunology; innate immunity; signal transducer and activator of transcription 3