Airway epithelial cells activate TH2 cytokine production in mast cells through IL-1 and thymic stromal lymphopoietin

Background: Airway epithelial cells are important regulators of innate and adaptive immunity. Although mast cells are known to play a central role in manifestations of allergic inflammation and are found in the epithelium in patients with T(H)2-related diseases, their role is incompletely understood. Objectives: The objective of this study was to investigate the role of airway epithelial cells in the production of T(H)2 cytokines in mast cells. Methods: Normal human bronchial epithelial (NHBE) cells were stimulated with TNF, IL-4, IFN-gamma, IL-17A, and double-stranded RNA (dsRNA) alone or in combination. Human mast cells were stimulated with epithelial cell-derived supernatants or cocultured with NHBE cells. T(H)2 cytokine responses were blocked with neutralizing antibodies. Results: Supernatants from IL-4- and dsRNA-stimulated NHBE cells significantly enhanced T(H)2 cytokine production from mast cells. The combination of IL-4 and dsRNA itself or supernatants from NHBE cells stimulated with other cytokines did not activate mast cells, suggesting that mast cell responses were induced by epithelial cell factors that were only induced by IL-4 and dsRNA. Epithelial supernatant-dependent T(H)2 cytokine production in mast cells was suppressed by anti-IL-1 and anti- thymic stromal lymphopoietin (TSLP) and was enhanced by anti-IL-1 receptor antagonist. Similar results were observed in coculture experiments. Finally, we found dsRNA-dependent production of IL-1, TSLP, and IL-1 receptor antagonist in NHBE cells was regulated by T-H cytokines, and their ratio in NHBE cells correlated with T(H)2 cytokine production in mast cells. Conclusions: Pathogens producing dsRNA, such as respiratory viral infections, might amplify local T(H)2 inflammation in asthmatic patients through the production of TSLP and IL-1 by epithelial cells and subsequent activation of T(H)2 cytokine production by mast cells in the airways. (J Allergy Clin Immunol 2012; 130: 225-32.)