title: Loss of IL-4Rα-mediated PI3K signaling accelerates the progression of IgE/mast cell-mediated reactions.
abstract: 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.
authors.affiliation: Divisions of Allergy and Immunology and of Immunobiology Department of Pediatrics University of Cincinnati College of Medicine Cincinnati Children's Hospital Medical Center 3333 Burnet Avenue Cincinnati OH 45229.
authors.forename: Jane
authors.initials: J
authors.lastname: Sledd
authors.affiliation: Divisions of Allergy and Immunology and of Immunobiology Department of Pediatrics University of Cincinnati College of Medicine Cincinnati Children's Hospital Medical Center 3333 Burnet Avenue Cincinnati OH 45229.
authors.forename: David
authors.initials: D
authors.lastname: Wu
authors.affiliation: Divisions of Allergy and Immunology and of Immunobiology Department of Pediatrics University of Cincinnati College of Medicine Cincinnati Children's Hospital Medical Center 3333 Burnet Avenue Cincinnati OH 45229.
authors.forename: Richard
authors.initials: R
authors.lastname: Ahrens
authors.affiliation: Divisions of Allergy and Immunology and of Immunobiology Department of Pediatrics University of Cincinnati College of Medicine Cincinnati Children's Hospital Medical Center 3333 Burnet Avenue Cincinnati OH 45229.
authors.forename: Jeebong
authors.initials: J
authors.lastname: Lee
authors.affiliation: Divisions of Allergy and Immunology and of Immunobiology Department of Pediatrics University of Cincinnati College of Medicine Cincinnati Children's Hospital Medical Center 3333 Burnet Avenue Cincinnati OH 45229.
authors.forename: Lisa
authors.initials: L
authors.lastname: Waggoner
authors.affiliation: Divisions of Allergy and Immunology and of Immunobiology Department of Pediatrics University of Cincinnati College of Medicine Cincinnati Children's Hospital Medical Center 3333 Burnet Avenue Cincinnati OH 45229.
authors.forename: Ying Ting
authors.initials: YT
authors.lastname: Tsai
authors.affiliation: Divisions of Allergy and Immunology and of Immunobiology Department of Pediatrics University of Cincinnati College of Medicine Cincinnati Children's Hospital Medical Center 3333 Burnet Avenue Cincinnati OH 45229.
authors.forename: Yui-Hsi
authors.initials: YH
authors.lastname: Wang
authors.affiliation: Divisions of Allergy and Immunology and of Immunobiology Department of Pediatrics University of Cincinnati College of Medicine Cincinnati Children's Hospital Medical Center 3333 Burnet Avenue Cincinnati OH 45229.
authors.forename: Simon P
authors.initials: SP
authors.lastname: Hogan
keywords: IgE and mast cells; food‐induced anaphylaxis; interleukin 4 (IL‐4) receptor (IL‐4R) chain