title: IL-33 is a mediator rather than a trigger of the acute allergic response in humans.
abstract: BACKGROUND
  IL-33 enhances FcεRI-induced mediator release in human basophils without inducing degranulation itself. In contrast, studies in mice suggested that in the presence of high IgE levels, IL-33 triggers degranulation and anaphylaxis of similar severity as specific allergen. Consistent with this view, sera of atopic patients contain elevated levels of IL-33 after anaphylaxis. In this study, we determined whether IL-33 is potentially anaphylactogenic in humans with high IgE levels by regulating exocytosis independent of FcεRI cross-linking. Furthermore, we investigated whether IL-33 is released upon allergen provocation in vivo.
  
  
  METHODS
  In subjects with high serum IgE levels, we measured IL-33-induced histamine/LTC4 in vitro, CD63 translocation ex vivo, and responsiveness of mast cells in vivo by skin prick test (SPT). In asthma patients, release of IL-33 and its correlation with early (tryptase)- and late-phase markers (IL-13 levels, eosinophil numbers) of the allergic response were assessed in bronchoalveolar lavage fluids (BALFs) after allergen challenge.
  
  
  RESULTS
  IL-33 itself does not trigger basophil degranulation in vitro and ex vivo, even in subjects with high serum IgE levels, and negative SPTs demonstrate that skin mast cells do not degranulate in response to IL-33. However, in response to allergen challenge, IL-33 is rapidly released into BALFs at levels that do not correlate with other immediate- and late-phase parameters.
  
  
  CONCLUSIONS
  IL-33 is unlikely an independent trigger of anaphylaxis even in subjects with high IgE levels. However, the rapid release of IL-33 upon allergen provocation in vivo supports its role as a mediator of immediate allergic responses.
authors.affiliation: Institute of Immunology, University Hospital Bern, Inselspital, Bern, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Fux
authors.forename: T
authors.initials: T
authors.lastname: Pecaric-Petkovic
authors.forename: A
authors.initials: A
authors.lastname: Odermatt
authors.forename: O V
authors.initials: OV
authors.lastname: Hausmann
authors.forename: A
authors.initials: A
authors.lastname: Lorentz
authors.forename: S C
authors.initials: SC
authors.lastname: Bischoff
authors.forename: J C
authors.initials: JC
authors.lastname: Virchow
authors.forename: C A
authors.initials: CA
authors.lastname: Dahinden
mesh_terms: D000208:Acute Disease; D015549:Basophil Degranulation Test; D001985:Bronchial Provocation Tests; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D015550:Cell Degranulation / Q000276:immunology*; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology*; D000067596:Interleukin-33; D007378:Interleukins / Q000276:immunology*; D008407:Mast Cells / Q000276:immunology*; D012882:Skin Tests
chemical_list: C506536:IL33 protein, human; D000067596:Interleukin-33; D007378:Interleukins
keywords: IL-33; IgE; asthma; basophil/mast cell degranulation; bronchoalveolar lavage fluids