Synthesis of tenascin and laminin beta2 chain in human bronchial epithelial cells is enhanced by cysteinyl leukotrienes via CysLT1 receptor.
BACKGROUND
Cysteinyl leukotrienes (CysLTs) are key mediators of asthma, but their role in the genesis of airway remodeling is insufficiently understood. Recent evidence suggests that increased expression of tenascin (Tn) and laminin (Ln) beta2 chain is indicative of the remodeling activity in asthma, but represents also an example of deposition of extracellular matrix, which affects the airway wall compliance. We tested the hypothesis that CysLTs affect production of Tn and Ln beta2 chain by human bronchial epithelial cells and elucidated, which of the CysLT receptors, CysLT1 or CysLT2, mediate this effect.


METHODS
Cultured BEAS-2B human bronchial epithelial cells were stimulated with leukotriene D4 (LTD4) and E4 (LTE4) and evaluated by immunocytochemistry, Western blotting, flow cytometry, and RT-PCR. CysLT receptors were differentially blocked with use of montelukast or BAY u9773.


RESULTS
LTD4 and LTE4 significantly augmented the expression of Tn, whereas LTD4, distinctly from LTE4, was able to increase also the Ln beta2 chain. Although the expression of CysLT2 prevailed over that of CysLT1, the up-regulation of Tn and Ln beta2 chain by CysLTs was completely blocked by the CysLT1-selective antagonist montelukast with no difference between montelukast and the dual antagonist BAY u9773 for the inhibitory capacity.


CONCLUSIONS
These findings suggest that the CysLT-induced up-regulation of Tn and Ln beta2 chain, an important epithelium-linked aspect of airway remodeling, is mediated predominantly by the CysLT1 receptor. The results provide a novel aspect to support the use of CysLT1 receptor antagonists in the anti-remodeling treatment of asthma.
Altraja
Siiri
S
Department of Pulmonary Medicine, University of Tartu, Tartu, Estonia. siiri.altraja@ut.ee
Kadai
Martin
M
Rekker
Erki
E
Altraja
Alan
A
D015153:Blotting, Western; D001980:Bronchi / Q000166:cytology*; D018929:Cell Culture Techniques; D004847:Epithelial Cells / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D007797:Laminin / Q000096:biosynthesis*; D018077:Receptors, Leukotriene / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019063:Tenascin / Q000096:biosynthesis* / Q000235:genetics
D007797:Laminin; D018077:Receptors, Leukotriene; D019063:Tenascin; C058783:laminin beta2; C083169:leukotriene D4 receptor