IL-33 enhances responsiveness and mast cell mediator release in isolated human small airways.

Abstract

Concomitant exposure to IL-33, thymic stromal lymphopoietin (TSLP), and IL-25 augments antigen-induced contractions of isolated human small bronchi through enhanced mast cell reactivity. We sought to test the individual contribution of alarmins in antigen-induced airway hyperresponsiveness and hyperosmolarity-induced responses evoked by mannitol, a surrogate model of exercise-induced bronchoconstriction. Intact segments of small airways, isolated from fresh human lung tissue, were incubated with IL-33, TSLP, IL-25, or buffer control for 48 hours. Contractile responses to anti-IgE or mannitol were then assessed using myograph systems. Mast cell degranulation and mediator release were analyzed both from the bronchial segments and from isolated primary human lung mast cells as well as from the human mast cell line LAD2 (Laboratory of Allergic Diseases 2). IL-33 increased contractile force (E_max) to anti-IgE and hyperosmolar mannitol by 62% and 78%, respectively. IL-33 also doubled antigen-IgE-induced prostaglandin D₂ release from bronchial segments as well as enhanced degranulation, cysteinyl leukotriene, and prostaglandin D₂ release from isolated human lung mast cells stimulated by anti-IgE or mannitol. In contrast, TSLP and IL-25 had no effect on contraction, degranulation, or mediator release in response to either stimulus. IL-33, but not TSLP or IL-25, enhances bronchoconstriction in human small bronchi by amplifying mast cell activation and mediator release in response to both antigen and hyperosmolar challenge.