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) beta 2 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 beta 2 chain by human bronchial epithelial cells and elucidated, which of the CysLT receptors, CysLT(1) or CysLT(2), mediate this effect. Methods: Cultured BEAS-2B human bronchial epithelial cells were stimulated with leukotriene D-4 (LTD4) and E-4 (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 beta 2 chain. Although the expression of CysLT2 prevailed over that of CysLT1, the up-regulation of Tn and Ln beta 2 chain by CysLTs was completely blocked by the CysLT(1)-selective antagonist montelukast with no difference between montelukast and the dual antagonist BAY u9773 for the inhibitory capacity. Conclusion: These findings suggest that the CysLT-induced up-regulation of Tn and Ln beta 2 chain, an important epithelium-linked aspect of airway remodeling, is mediated predominantly by the CysLT(1) receptor. The results provide a novel aspect to support the use of CysLT(1) receptor antagonists in the anti-remodeling treatment of asthma.