Proteases induce production of thymic stromal lymphopoietin by airway epithelial cells through protease-activated receptor-2.
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.
Kouzaki
Hideaki
H
Division of Allergic Diseases, Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA.
O'Grady
Scott M
SM
Lawrence
Christopher B
CB
Kita
Hirohito
H
D000485:Allergens / Q000494:pharmacology; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism*; D006801:Humans; D010206:Papain / Q000494:pharmacology; D010447:Peptide Hydrolases / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D044464:Receptor, PAR-2 / Q000502:physiology*; D012137:Respiratory System / Q000166:cytology / Q000378:metabolism*; D015533:Transcriptional Activation; D014357:Trypsin / Q000494:pharmacology; D000094632:Thymic Stromal Lymphopoietin
D000485:Allergens; D016207:Cytokines; D012333:RNA, Messenger; D044464:Receptor, PAR-2; D010447:Peptide Hydrolases; D014357:Trypsin; D010206:Papain; D000094632:Thymic Stromal Lymphopoietin