STAT3 plays a critical role in histamine-induced vascular permeability

Tuesday, September 23, 2014 — Poster Session III
12:00 p.m. – 2:00 p.m.	FAES Academic Center	NIAID	IMMUNO-13

Authors

• M O'Connell
• V Hox
• A Olivera
• D Metcalfe
• J Milner

Abstract

During IgE-mediated immediate hypersensitivity reactions, mediators such as histamine are released from mast cells and act on vascular endothelial cells to increase permeability which ultimately can lead to anaphylaxis. Previously, we observed that patients with STAT3 mutations are protected from anaphylaxis. We therefore sought to determine whether the mechanisms by which STAT3 mutation prevents anaphylaxis. Treatment with histamine lead to an increase in permeability of human umbilical vein vascular endothelial cells (HUVECS) from controls, but not HIES patients or HUVECs treated with the STAT3 inhibitor C188-9. Further, we demonstrated C188-9 treatment or STAT3 mutation increases basal levels of VE-Cadherin and beta-catenin in HUVEC cells. Treatment with histamine decreased VE-cadherin and total/active beta-catenin in DMSO treated cells but not HIES HUVECS or cells treated with C188-9. In vivo treatment of healthy mice with C188-9 prevents IgE and histamine-induced anaphylaxis. Taken together, our results demonstrate a surprising but important role for STAT3 in inducing vascular endothelial cells permeability, and suggests that small molecule inhibition of STAT3 can prevent anaphylaxis.

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