Proteases Induce Production of Thymic Stromal Lymphopoietin by Airway Epithelial Cells through Protease-Activated Receptor-2

• Published in: The Journal of immunology (1950) 2009-07, Vol.183 (2), p.1427-1434
• Main Authors: Kouzaki, Hideaki, O'Grady, Scott M, Lawrence, Christopher B, Kita, Hirohito
• Format: Article
• Language: English
• Subjects: Allergens - pharmacology; Cell Line; Cytokines - biosynthesis; Cytokines - genetics; Epithelial Cells - metabolism; Humans; Papain - pharmacology; Peptide Hydrolases - pharmacology; Receptor, PAR-2 - physiology; Respiratory System - cytology; Respiratory System - metabolism; RNA, Messenger - biosynthesis; Transcriptional Activation; Trypsin - pharmacology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.0900904

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-gamma. 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.