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Leukotriene D4-induced, epithelial cell-derived transforming growth factor β1 in human bronchial smooth muscle cell proliferation


Dr M. Rola-Pleszczynski, Immunology Division, Department of Pediatrics, Faculty of Medicine, Université de Sherbrooke 3001, North 12th Avenue, Sherbrooke, QC, Canada J1H 5N4.


Background Cysteinyl-leukotrienes (cys-LTs) orchestrate many pathognomonic features of asthma in animal models of allergic airway inflammation, including bronchial smooth muscle cell (BSMC) hyperplasia. However, because cys-LTs alone do not induce mitogenesis in monocultures of human BSMC, the effect observed in vivo seemingly involves indirect mechanisms, which are still undefined.

Objective This study aims to investigate the regulatory role of leukotriene (LT)D4 on TGF-β1 expression in airway epithelial cells and the consequence of this interplay on BSMC proliferation.

Methods HEK293 cells stably transfected with cys-LT receptor 1 (CysLT1) (293LT1) were stimulated with LTD4 and TGF-β1 mRNA and protein expression was measured using Northern blot and ELISA, respectively. Conditioned medium (CM) harvested from LTD4-treated cells was then assayed for its proliferative effect on primary human BSMC. TGF-β1 mRNA expression was also determined in tumoural type II pneumocytes A549 and in normal human bronchial epithelial cells (NHBE) following LTD4 stimulation.

Results The results demonstrated that LTD4-induced TGF-β1 mRNA production in a time- and concentration-dependent manner in 293LT1. TGF-β1 secretion was also up-regulated and CM from LTD4-treated 293LT1 was shown to increase BSMC proliferation in a TGF-β1-dependent manner. The increased expression of TGF-β1 mRNA by LTD4 also occured in A549 and NHBE cells via a CysLT1-dependent mechanism.

Conclusion In conclusion, elevated expression of cys-LTs in asthmatic airways might contribute to BSMC hyperplasia and concomitant clinical features of asthma such as airway hyperresponsiveness via a paracrine loop involving TGF-β1 production by airway epithelial cells.