Open AccessLoss of IL‐4Rα–mediated PI3K signaling accelerates the progression of IgE/mast cell–mediated reactions
Author(s) -
Sledd Jane,
Wu David,
Ahrens Richard,
Lee Jeebong,
Waggoner Lisa,
Tsai Ying Ting,
Wang YuiHsi,
Hogan Simon P.
Publication year - 2015
Publication title -
immunity, inflammation and disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.918
H-Index - 18
ISSN - 2050-4527
DOI - 10.1002/iid3.80
Subject(s) - histamine , mast cell , immunoglobulin e , immunology , signal transduction , anaphylaxis , pi3k/akt/mtor pathway , biology , allergy , chemistry , microbiology and biotechnology , endocrinology , antibody
Clinical and experimental evidence indicate that polymorphisms within the interleukin 4 (IL‐4) receptor (IL‐4R) chain are sufficient for altered strength of IL‐4/IL‐13 signaling, leading to an exaggerated allergic inflammatory response and increase susceptibility to allergic phenotypes. In the present study, we show that ablation of IL‐4Rα–induced phosphatidylinositol 3‐kinase (PI3K) activating signal by germline point mutation within the IL‐4Rα motif (Y500F) did not alter susceptibility to IgE‐mediated, food‐induced experimental anaphylaxis. Moreover, diarrhea occurrence, antigen‐specific IgE and intestinal mastocytosis were comparable between WT and IL‐4Rα Y500F mice. However, mice unable to stimulate IL‐4Rα–mediated PI3K signaling had accelerated disease progression. Notably, the accelerated anaphylactic response was associated with more rapid histamine‐induced hypovolemia. Mechanistic in vitro and in vivo analyses revealed that endothelial IL‐4Rα PI3K signaling negatively regulates the histamine‐induced endothelial leak response. These results define an unanticipated role for IL‐4Rα–mediated PI3K signaling in negative regulation of IgE‐mediated anaphylactic reactions.