title: Direct effects of IL-4 on mast cells drive their intestinal expansion and increase susceptibility to anaphylaxis in a murine model of food allergy.
abstract: Interleukin (IL)-4 has critical roles in allergic disorders, including food hypersensitivity. The direct effects of the cytokine on the survival and function of mast cells, the key effectors of food anaphylaxis, have not been established. In this study, we demonstrate that IL-4 induces a marked intestinal mastocytosis in mice. This phenotype is reproduced in animals expressing Il4rαF709, an activating variant of the IL-4 receptor α-chain (IL-4Rα). Il4rαF709 mice exhibit enhanced anaphylactic reactions but unaltered physiological responses to vasoactive mediators. IL-4 induces Bcl-2 and Bcl-X(L) and enhances survival and stimulates proliferation in cultured bone marrow-derived mast cells (BMMC). These effects are STAT6 (signal transducer and activator of transcription factor 6)-dependent and are amplified in Il4rαF709 BMMC. In competitive bone marrow chimeras, Il4rαF709 mast cells display a substantial competitive advantage over wild-type mast cells, which, in turn, prevail over IL-4Rα⁻/⁻ mast cells in populating the intestine, establishing a cell-intrinsic effect of IL-4 in intestinal mast cell homeostasis. Our results demonstrate that IL-4-signaling is a key determinant of mast cell expansion in food allergy.
authors.affiliation: Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA.
authors.forename: O T
authors.initials: OT
authors.lastname: Burton
authors.forename: A R
authors.initials: AR
authors.lastname: Darling
authors.forename: J S
authors.initials: JS
authors.lastname: Zhou
authors.forename: M
authors.initials: M
authors.lastname: Noval-Rivas
authors.forename: T G
authors.initials: TG
authors.lastname: Jones
authors.forename: M F
authors.initials: MF
authors.lastname: Gurish
authors.forename: T A
authors.initials: TA
authors.lastname: Chatila
authors.forename: H C
authors.initials: HC
authors.lastname: Oettgen
mesh_terms: D000707:Anaphylaxis / Q000235:genetics / Q000276:immunology*; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D004195:Disease Models, Animal; D004198:Disease Susceptibility / Q000276:immunology; D005512:Food Hypersensitivity / Q000235:genetics / Q000276:immunology*; D015847:Interleukin-4 / Q000378:metabolism* / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000276:immunology*; D008407:Mast Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D017455:Receptors, IgE / Q000378:metabolism; D019948:Receptors, Interleukin-4 / Q000235:genetics / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D017455:Receptors, IgE; D019948:Receptors, Interleukin-4; D050800:STAT6 Transcription Factor; D015847:Interleukin-4