IL-33 is sufficient to induce eosinophilic airway inflammation, and exacerbates established inflammation, through increased ST2 dependent local Th2 cytokine and chemokine production

Kewin, P., Kurowska-Stolarska, M. , Murphy, G., Pitman, N., ChooKang, B., Patel, M., Xu, D., Liew, F.Y. and Thomson, N. (2007) IL-33 is sufficient to induce eosinophilic airway inflammation, and exacerbates established inflammation, through increased ST2 dependent local Th2 cytokine and chemokine production. In: Winter Meeting of the British-Thoracic-Society, London, UK, 05-07 Dec 2007, A1.

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Publisher's URL: http://thorax.bmj.com/content/62/Suppl_3.toc

Abstract

Introduction: The key pathological features of asthma are eosinophilic airway inflammation, mucus hypersecretion and airway remodelling, mediated by Th2 cytokines (IL-4, IL-5, IL-13). IL-4 or IL-13 administered directly to the airways are sufficient to induce these pathological features independent of antigen (Grunig G et al, Science 1998; Wills-Karp et al, Science 1998). IL-33 is a novel cytokine which binds to the orphan ST2 receptor and induces Th2 cytokine expression (Schmitz et al, Immunity 2005). We hypothesised that IL-33 would be sufficient to induce eosinophilic airway inflammation, and may exacerbate antigen-specific allergic airway inflammation.

Methods: The antigen-independent effect of IL-33 was assessed by administering PBS ± recombinant (r)IL-33 intranasally (i.n.) to BALB/c mice for 7 consecutive days. Bronchoalveolar lavage (BAL) was performed 24 h later. Differential cell counts were performed on cytopreps, and the concentration of BAL cytokines and chemokines determined by ELISA. Lungs were obtained for histological assessment. Allergic airway inflammation was induced in BALB/c mice by intraperitoneal (i.p.) sensitisation with ovalbumin (OVA) and alum on day 1, followed by i.n. challenge on days 9 and 11 with OVA ± rIL-33. Mice were analysed as above, and ST2 gene knockout mice were used to demonstrate the specificity of action of rIL-33.

Results: rIL-33 induced marked eosinophilic inflammation (fig A). BAL eosinophils (data not shown), cytokines (IL-5 and IL-13, but not IL-4) and chemokines (eotaxin-1, eotaxin-2 and TARC) were increased (table). Airway challenge with OVA following sensitisation induced eosinophilic inflammation, which was increased markedly by rIL-33 (fig B), as were BAL eosinophils, cytokines and chemokines (table). IL-33 had no effect in ST2KO mice in either model.

Conclusions: rIL-33 in the absence of antigen induced airway pathology very similar to that of experimental asthma. This was mediated by local induction of Th2 associated cytokines and chemokines, with the exception of IL-4, and was dependent on ST2 expression. In addition, IL-33 exacerbated allergic airway inflammation by a similar mechanism. Thus IL-33/ST2 represents an important mechanism of IL-4-independent airway inflammation, and represents a novel target for therapeutic intervention during both the initiation and maintenance phases of allergic asthma.

Item Type:Conference Proceedings
Additional Information:Special Issue: Thorax, 62(A3):A1
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Liew, Professor Foo and Xu, Dr Damo and Thomson, Professor Neil and Kurowska-Stolarska, Dr Mariola
Authors: Kewin, P., Kurowska-Stolarska, M., Murphy, G., Pitman, N., ChooKang, B., Patel, M., Xu, D., Liew, F.Y., and Thomson, N.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Thorax
Publisher:BMJ Publishing Group
ISSN:0040-6376
ISSN (Online):1468-3296

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