Loss of IL-4Rα-mediated PI3K signaling accelerates the progression of IgE/mast cell-mediated reactions.

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.