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J. Biol. Chem., Vol. 281, Issue 11, 6910-6923, March 17, 2006

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The House Dust Mite Allergen Der p 1, Unlike Der p 3, Stimulates the Expression of Interleukin-8 in Human Airway Epithelial Cells via a Proteinase-activated Receptor-2-independent Mechanism^*

Emmanuelle Adam, Kristina K. Hansen, Olaya Fernandez Astudillo, Ludivine Coulon, Françoise Bex^¶, Xavier Duhant^||, Erika Jaumotte, Morley D. Hollenberg, and Alain Jacquet¹

From the Department of Applied Genetics, Institut de Biologie et de Médecine Moléculaires, Université Libre de Bruxelles, B-6041 Gosselies, Belgium, the Canadian Institutes of Health Research Proteinases and Inflammation Network, Departments of Pharmacology and Therapeutics and Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada, ^¶Laboratoire de Microbiologie, Institut CERIA, Université Libre de Bruxelles, 1060 Brussels, Belgium, and the ^||Institute of Interdisciplinary Research, School of Medecine, Department of Immunology, Erasme Hospital, Université Libre de Bruxelles, 1060 Brussels, Belgium

We investigated and compared the mechanisms by which two dust mite proteolytic allergens, Der p 1 and Der p 3, and a peptide agonist of proteinase-activated receptor 2 (PAR₂AP) trigger interleukin (IL)-8 release from human pulmonary epithelial cells (A549). Although all three stimuli tested induced the up-regulation of IL-8 (mRNA and protein), the Der p 1-mediated signaling events did not exactly match those induced by PAR₂AP and Der p 3. First, Der p 1 was less effective in stimulating IL-8 gene transcriptional activity than PAR₂AP and Der p 3. Second, Der p 1-mediated IL-8 expression was mainly dependent on NF-B, whereas Der p 3 and PAR₂AP regulated IL-8 expression through the activation of both NF-B and AP-1. Third, although all three MAP kinases, ERK1/2, p38, and JNK, were activated, Der p 1 induced IL-8 release exclusively via the ERK1/2 signaling pathway, whereas PAR₂AP and Der p 3 also involved the other kinases. Fourth, in HeLa cells, Der p 1 was able to up-regulate IL-8 secretion independent of PAR₂ expression, and in contrast with PAR₂AP and Der p 3, Der p 1 was unable to affect calcium signaling via PAR₂ in PAR₂-expressing KNRK cells. Finally, cleavage by Der p 1 of a synthetic peptide representing the N-terminal activation-cleavage site of PAR₂ did not release a high potency activator of PAR₂ as does Der p 3. We conclude that Der p 1 (but not Der p 3)-induced IL-8 production in A549 epithelial cells is independent of PAR₂ activation.

Received for publication, June 30, 2005 , and in revised form, October 12, 2005.

^* This work was supported in part by GlaxoSmithKline (Rixensart, Belgium), by the Walloon Region (Direction Générales des Technologies, de la Recherche, et de l'Energie) of Belgium, by a term grant from the Canadian Institutes of Health Research (to M. D. H.), and by a postdoctoral fellowship from the Alberta Heritage Foundation for Medical Research (to K. K. H.). 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 To whom correspondence should be addressed: Dept. of Applied Genetics, Rue des Professeurs Jeener et Brachet, 12, B-6041 Gosselies, Belgium. Tel.: 32-2-650-99-09; Fax: 32-2-650-99-00; E-mail: alain.jacquet{at}ulb.ac.be.

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