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This Article Full Text (PDF) All Versions of this Article: jimmunol.0900904v1 183/2/1427    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Kouzaki, H. Articles by Kita, H. PubMed PubMed Citation Articles by Kouzaki, H. Articles by Kita, H.

Proteases Induce Production of Thymic Stromal Lymphopoietin by Airway Epithelial Cells through Protease-Activated Receptor-2¹

Hideaki Kouzaki^*,, Scott M. O'Grady^,, Christopher B. Lawrence^¶ and Hirohito Kita^*,2

*Division of Allergic Diseases, Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905; Department of Otorhinolaryngology, Shiga University of Medical Science, Otsu, Shiga, Japan; Department of Integrated Biology and Department of Physiology and Animal Science, University of Minnesota, St. Paul, MN 55108; and ^¶Virginia Bioinformatics Institute and Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061

Thymic stromal lymphopoietin (TSLP) is produced by epithelial cells and triggers dendritic cell-mediated Th2-type inflammation. Although TSLP is up-regulated in epithelium of patients with asthma, the factors that control TSLP production have not been studied extensively. Because mouse models suggest roles for protease(s) in Th2-type immune responses, we hypothesized that proteases from airborne allergens may induce TSLP production in a human airway epithelial cell line, BEAS-2B. TSLP mRNA and protein were induced when BEAS-2B cells were exposed to prototypic proteases, namely, trypsin and papain. TSLP induction by trypsin required intact protease activity and also a protease-sensing G protein-coupled receptor, protease-activated receptor (PAR)-2; TSLP induction by papain was partially dependent on PAR-2. In humans, exposure to ubiquitous airborne fungi, such as Alternaria, is implicated in the development and exacerbation of asthma. When BEAS-2B cells or normal human bronchial epithelial cells were exposed to Alternaria extract, TSLP was potently induced. The TSLP-inducing activity of Alternaria was partially blocked by treating the extract with a cysteine protease inhibitor, E-64, or by infecting BEAS-2B cells with small interfering RNA for PAR-2. Protease-induced TSLP production by BEAS-2B cells was enhanced synergistically by IL-4 and abolished by IFN-. These findings demonstrate that TSLP expression is induced in airway epithelial cells by exposure to allergen-derived proteases and that PAR-2 is involved in the process. By promoting TSLP production in the airways, proteases associated with airborne allergens may facilitate the development and/or exacerbation of Th2-type airway inflammation, particularly in allergic individuals.

²Address correspondence and reprint requests to Dr. Hirohito Kita,Division of Allergic Diseases, Mayo Clinic, Rochester, MN 55905. E-mail address: kita.hirohito{at}mayo.edu

¹ This work was supported in part by the National Institutes of Health, National Institute of Allergy and Infectious Diseases (Grant AI49235) and the Mayo Foundation.