IL-33, but Not TSLP, Augments Carbachol-Induced Bronchoconstriction and Attenuates Formoterol-Induced Bronchodilation of Human Small Airways

Rationale: IL-33 and TSLP, epithelium-derived Th2 cytokines, have been impugned in the pathogenesis of asthma and exacerbations. These cytokines affect maturation and migration of immune cells. However, effects of IL-33 and TSLP on airway contractility have not been well defined. We previously demonstrated that IL-13, another Th2 cytokine, augments contractility and attenuates dilation of airways in human precision cut lung slices (hPCLS). Therefore, we posit that both IL-33 and TSLP augment contractility and attenuate dilation of hPCLS.

Methods: hPCLS were exposed to TSLP or IL-33 (1, 10, 100 nM – 24 hr) and bronchoconstriction carbachol (Cch, 10^-8 – 10^-4 M), as well as bronchodilation to formoterol (Form, 10^-9 – 10^-4 M) were measured. Log EC50 for contraction and dilation following cytokine exposure were compared to control buffer stimulation.

Results: Airway responsiveness to Cch following stimulation with IL-33, but not TSLP, was augmented in hPCLS (LogEC50: control vs 100 nM TSLP, -0.56 vs -1.55 μM, p=ns; control vs 100 nM IL-33, -0.56 vs -2.02 μM, p=0.01). Airway dilation to Form following stimulation with IL-33, but not TSLP, was attenuated in hPCLS (LogEC50: control vs 100 nM TSLP, -1.70 vs -1.73 μM, p=ns; control vs 100 nM IL-33, -1.70 vs 1.97 μM, p=0.003).

Conclusions: We show that the Th2 cytokine IL-33 modulates agonist-induced bronchoconstriction and bronchodilation, but TSLP has little effect. These data suggest that IL-33 may play a role in the airway hyperresponsiveness observed following allergen or virus exposure, providing a target for therapy of allergic asthma and asthma exacerbations.