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

详细信息    查看全文

• 作者：Valerie Hox ; MD ; PhD^a ; ^&lowast ; ; Michael P. O'Connell ; PhD^a ; ^&lowast ; ; Jonathan J. Lyons ; MD^a ; Paul Sackstein ; BS^a ; Thomas Dimaggio ; ADN ; RN^a ; Nina Jones ; BSN ; RN^d ; Celeste Nelson ; MS CRNP^a ; Manfred Boehm ; MD^c ; Steven M. Holland ; MD^b ; Alexandra F. Freeman ; MD^b ; David J. Tweardy ; MD^e ; Ana Olivera ; PhD^a ; Dean D. Metcalfe ; MD^a ; ^&Dagger ; ; Joshua D. Milner ; MD^a ; ^&Dagger ; ; ^{jdmilner@niaid.nih.gov" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Allergy ; immunology ; innate immunity ; signal transducer and activator of transcription 3 ; autosomal dominant hyper-IgE syndrome
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2016
• 出版时间：July 2016
• 年：2016
• 卷：138
• 期：1
• 页码：187-199
• 全文大小：2868 K

文摘

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.