Pharmacological Research 70 (2013) 50–59 Contents lists available at SciVerse ScienceDirect Pharmacological Research jo u r n al hom epage: www.elsevier.com/locat e/yphrs Locally administered prostaglandin E2 prevents aeroallergen-induced airway sensitization in mice through immunomodulatory mechanisms Rosa Torres a,b,∗,1 , Aida Herrerias a,1,2 , Mariona Serra-Pagès a , Alberto Marco c , Judith Plaza a , Cristina Costa-Farré c , María Montoya d , César Picado e,b , Fernando de Mora a a Department of Pharmacology, Universitat Autònoma de Barcelona, Barcelona, Spain b CIBER (Centro de Investigación Biomédica en Red) de Enfermedades Respiratorias, Spain c Department of Animal Pathology, Universitat Autònoma de Barcelona, Barcelona, Spain d Centre de Recerca en Sanitat Animal (CReSA), UAB-IRTA, Campus de la Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain e Department of Pneumology and Respiratory Allergy, Hospital Clínic, IDIBAPS, Universitat de Barcelona, Barcelona, Spain a r t i c l e i n f o Article history: Received 1 August 2012 Received in revised form 10 December 2012 Accepted 10 December 2012 Keywords: Aeroallergen sensitization Immunomodulation Plasmacytoid dendritic cells Prostaglandin E2 a b s t r a c t Prostaglandin E2 attenuates airway pathology in asthmatic patients and exerts a protective effect in antigen-sensitized mice when administered systemically. We aimed to establish the consequences of intranasal PGE2 administration on airway reactivity to aeroallergens in mice and reveal the underlying immunoinflammatory mechanisms. PGE2 was administered either daily during a 10-day exposure to house dust mite (HDM) extracts or for limited intervals. Airway hyperreactivity was measured by whole-body and invasive plethysmography. The phenotypes of lung immune cells and cytokine production were analysed by flow cytometry and ELISA, respectively. Airway hyperreactivity was sustainably reduced only when PGE2 administration was restricted to the initial 5 days of exposure to HDM. Lung inflammation, IL-4 production, and airway mast cell activity were also prevented under this early short-term treatment with PGE2. Interestingly, a Th2 response was already committed on day 5 of exposure to HDM. This was paralleled by GM-CSF and osteopontin upregulation and a decreased number of plasmacytoid dendritic and T regulatory cells, as well as a trend towards reduced IL-10 expression. Local PGE2 administration prevented the increase of airway IL-13 and osteopontin and kept lung plasmacytoid dendritic cell counts close to baseline. GM-CSF and Tregs were unaffected by the treatment. These findings suggest that the protection provided by PGE2 is a result of the modulation of early lung immunomodulatory mechanisms, and possibly a shift in the balance of dendritic cells towards a tolerogenic profile. © 2013 Elsevier Ltd. All rights reserved. 1. Introduction Current treatments of allergic asthma do not halt the underlying process and are often unable to control the symptoms of the dis- ease. The fact that endogenous-like compounds, such as synthetic Abbreviations: PGE2, prostaglandin E2; HDM, house dust mite; pDC, plasmacy- toid DC; mDC, myeloid DC; OPN, osteopontin; AHR, airway hyperresponsiveness; MC, mast cell; mMCP-1, mouse mast cell protease-1; WBP, whole body plethysmo- graphy. ∗ Corresponding author at: Dpto. de Farmacología (Edificio V), Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain. Tel.: +34 93 5811683; fax: +34 93 5812959. E-mail address: rosa.torres@uab.cat (R. Torres). 1 These two authors contributed equally to this work. 2 Current address: R&D Division, Instituto Grifols, S.A, Polígono Levante, Parets del Vallès Barcelona, Spain. corticosteroids, remain the first-line treatment against asthma sets solid grounds for exploring natural protective pathways as an effi- cient strategy in search for new pharmacological targets. Local administration of prostaglandin (PG) E2, an endogenous molecule, to asthmatic patients challenged experimentally with allergens resulted in improved airway function and reduced inflammation [1–3]. In rodent models, we and others have shown that PGE2 alleviates ovalbumin (OVA)-driven inflammation, whereas COX- 2 blockade, which leads to reduced internal PGE2 production, increases airway reactivity [4–7]. We have recently reached similar conclusions using aeroallergen-sensitized mice [8,9]. Notably, we demonstrated that mice exposed to house dust mite (HDM) extracts were protected from airway hyperreactivity and inflammation when given subcutaneous PGE2. There is therefore substantial evidence highlighting a beneficial effect of PGE2 in the air- ways in vivo; however, little is known about the underlying mechanisms. 1043-6618/$ – see front matter © 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.phrs.2012.12.008