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

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:138

Article

Hox, Valerie¹  O'Connell, Michael P.¹  Lyons, Jonathan J.¹  Sackstein, Paul¹  Dimaggio, Thomas¹  Jones, Nina⁴  Nelson, Celeste¹  Boehm, Manfred³  Holland, Steven M.²  Freeman, Alexandra F.²  Tweardy, David J.⁵  Olivera, Ana¹  Metcalfe, Dean D.¹  Milner, Joshua D.¹ 

[1] NIAID, Lab Allerg Dis, NIH, Bethesda, MD USA

[2] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD USA

[3] NHLBI, Ctr Mol Med, NIH, Bethesda, MD USA

[4] Frederick Natl Lab Canc Res, Leidos Biomed Res, Clin Res Directorate CMRP, Frederick, MD USA

[5] Baylor Coll Med, Dept Med, Infect Dis Sect, Houston, TX USA

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

DOI  :  10.1016/j.jaci.2015.11.024

来源: Elsevier

【 摘 要 】

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 beta-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 beta-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.

【 授权许可】

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