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Proteinase-Activated Receptor-2 Promotes Allergic Sensitization to an Inhaled Antigen through a TNF-Mediated Pathway¹

Cory Ebeling^*, Tong Lam^*, John R. Gordon, Morley D. Hollenberg and Harissios Vliagoftis^2,*

^* Pulmonary Research Group, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada; Immunology Research Group, University of Saskatchewan, Saskatoon, Saskatchewan, Canada; and Department of Pharmacology and Therapeutics, University of Calgary, Calgary, Alberta, Canada

The reason why particular inhaled Ags induce allergic sensitization while others lead to immune tolerance is unclear. Along with a genetic predisposition to atopy, intrinsic characteristics of these Ags must be important. A common characteristic of many allergens is that they either possess proteinase activity or are inhaled in particles rich in proteinases. Many allergens, such as house dust mite and cockroach allergens, have the potential to activate the proteinase-activated receptor (PAR)-2. In this study, we report that PAR-2 activation in the airways at the same time as exposure to inhaled Ags induces allergic sensitization, whereas exposure to Ag alone induces tolerance. BALB/c mice were administered OVA with a PAR-2 activating peptide intranasally. Upon allergen re-exposure mice developed airway inflammation and airway hyperresponsiveness, as well as OVA-specific T cells with a Th2 cytokine profile when restimulated with OVA in vitro. Conversely, mice given OVA alone or OVA with a PAR-2 control peptide developed tolerance. These tolerant mice did not develop airway inflammation or airway hyperresponsiveness, and developed OVA-specific T cells that secreted high levels of IL-10 when restimulated with OVA in vitro. Furthermore, pulmonary dendritic cell trafficking was altered in mice following intranasal PAR-2 activation. Finally, we showed that PAR-2-mediated allergic sensitization was TNF-dependent. Thus, PAR-2 activation in the airways could be a critical factor in the development of allergic sensitization following mucosal exposure to allergens with serine proteinase activity. Interfering with this pathway may prove to be useful for the prevention or treatment of allergic diseases.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by funds from the Canadian Institutes of Health Research and Alberta Heritage Foundation for Medical Research. H.V. is an Alberta Heritage Foundation for Medical Research Scholar.

² Address correspondence and reprint requests to Dr. Harissios Vliagoftis, Pulmonary Research Group, Department of Medicine, 550 Heritage Medical Research Center, University of Alberta, Edmonton, Alberta T6G 2S2, Canada. E-mail address: harissios.vliagoftis{at}ualberta.ca

³ Abbreviations used in this paper: DC, dendritic cell; PAR, proteinase-activated receptor; PAR-2AP, PAR-2 activating peptide; PAR-2CP, PAR-2 control peptide; AHR, airway hyperresponsiveness; HDM, house dust mite; BAL, bronchoalveolar lavage; i.n., intranasally.

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